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WO2010017405A1 - Méthodes et compositions pour le traitement de la douleur - Google Patents

Méthodes et compositions pour le traitement de la douleur Download PDF

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Publication number
WO2010017405A1
WO2010017405A1 PCT/US2009/053024 US2009053024W WO2010017405A1 WO 2010017405 A1 WO2010017405 A1 WO 2010017405A1 US 2009053024 W US2009053024 W US 2009053024W WO 2010017405 A1 WO2010017405 A1 WO 2010017405A1
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WIPO (PCT)
Prior art keywords
bromo
acid
dibromo
pain
chloro
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Ceased
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PCT/US2009/053024
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English (en)
Inventor
Adam Heller
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Individual
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Individual
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/006—Sprayers or atomisers specially adapted for therapeutic purposes operated by applying mechanical pressure to the liquid to be sprayed or atomised
    • A61M11/007—Syringe-type or piston-type sprayers or atomisers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/06—Sprayers or atomisers specially adapted for therapeutic purposes of the injector type
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0001—Details of inhalators; Constructional features thereof
    • A61M15/0003—Details of inhalators; Constructional features thereof with means for dispensing more than one drug

Definitions

  • Chronic pain is one of the most important clinical problems in all of medicine. For example, it is estimated that over 5 million people in the United States are disabled by back pain. The economic cost of chronic back pain is enormous, resulting in over 100 million lost work days annually at an estimated cost of $50-100 billion. It has been reported that approximately 8 million people in the U.S. report that they experience chronic neck or facial pain and spend an estimated $2 billion a year for treatment. The cost of managing pain for oncology patients is thought to approach $12 billion. Chronic pain disables more people than cancer or heart disease and costs the American public more than both cancer and heart disease combined. In addition to the physical consequences, chronic pain has numerous other costs including loss of employment, marital discord, depression and prescription drug addiction.
  • Oxidizing agents are widely used as disinfectants.
  • oxidizing disinfectants include aqueous solutions of chlorine, where hypochlorite and hypochlorous acid co-exist near neutral pH; of iodine, often dissolved as potassium tri-iodide in potassium iodide containing solutions; of hydrogen peroxide; of N-chloro-compounds, like Chloramine-T, the sodium salt of N-chloro-p-toluenesulfonamide and its salts with other cations or like Chloramine-B, the sodium salt of N-chloro-benzenesulfonamide and its salts with other cations; and of chloramine, NH 2 Cl, also known as monochloramine; and of ozone.
  • Chlorine and the product of its reaction with water hypochlorous acid, and chloramine, as well as ozone, are widely used to disinfect municipal drinking water. Oxidizing agents are also applied in sterilization, for example of surgical instruments.
  • Oxidizing agents are also used in treatment of wounds and disease. Bactericidal oxidizing agents are used also to disinfect wounds, to prevent and control pathogen-caused inflammation, to assist in the healing of skin and other wounds, and to treat pathogen-caused diseases. When used to disinfect wounds, they are optionally topically applied, for example by swabbing, brushing, spraying, or in a dressing. They are applied topically also in order to prevent infection before the skin is purposely pierced or cut, for example, prior to an injection, withdrawal of a blood sample, or surgery.
  • oxidizing amines such as N-chlorinated amines and N-brominated amines, are useful for the treatment of pain and itch.
  • the invention features a device including: (i) a first chamber containing a first solution including an ammonium salt or an amine or a salt thereof; (ii) a second chamber containing a second solution including hypochlorous acid or a salt thereof; (iii) a mixing chamber for combining the first solution and the second solution to form an N-chlorinated amine; and (iv) a channel in fluid communication with the mixer chamber for delivering the N- chlorinated amine to a subject.
  • the invention features a device including: (i) a first chamber containing a first solution including an ammonium salt or an amine or a salt thereof; (ii) a second chamber containing a second solution including hypobromous acid or a salt thereof; (iii) a mixing chamber for combining the first solution and the second solution to form an N-brominated amine; and (iv) a channel in fluid communication with the mixer chamber for delivering the N- brominated amine to a subject.
  • the invention features a device including: (i) a first chamber containing a first solution including an ammonium salt or an amine or a salt thereof; (ii) a second chamber containing a second solution including (a) hypobromous acid, or a salt thereof, and (b) hypochlorous acid, or a salt thereof; (iii) a mixing chamber for combining the first solution and the second solution to form a mixture of N-brominated amine and N-chlorinated amine; and (iv) a channel in fluid communication with the mixer chamber for delivering the N-brominated amine and N-chlorinated amine to a subject.
  • the device is a three chamber device for mixing three solutions, the first solution including an ammonium salt or an amine or a salt thereof, the second solution including hypobromous acid, or a salt thereof, and the third solution including hypochlorous acid, or a salt thereof.
  • the three solutions are mixed in a mixing chamber to form a mixture of N-brominated amine and N- chlorinated amine.
  • the device is a syringe, a spray bottle, a spray canister, an irrigation bottle or bag.
  • the device may be gravity-driven, pressurized, or mechanically driven.
  • the invention features a device including: a double barrel syringe, the double barrel syringe having a plunger, a tip, a first barrel and a second barrel, the contents of the first and second barrels when mixed forming an N- chlorinated amine, the first barrel of the double barrel syringe including an amine, or a salt thereof, the second barrel of the double barrel syringe including hypochlorous acid, or a salt thereof.
  • the invention further features a device including: a double barrel syringe, the double barrel syringe having a plunger, a tip, a first barrel and a second barrel, the contents of the first and second barrels when mixed forming an N-brominated amine, the first barrel of the double barrel syringe including an amine, or a salt thereof, the second barrel of the double barrel syringe including hypobromous acid, or a salt thereof.
  • the invention further features a device including: a double barrel syringe, the double barrel syringe having a plunger, a tip, a first barrel and a second barrel, the contents of the first and second barrels when mixed forming a mixture of N-brominated amine and N-chlorinated amine, the first barrel of the double barrel syringe including an amine, or a salt thereof, the second barrel of the double barrel syringe including (a) hypobromous acid, or a salt thereof, and (b) hypochlorous acid, or a salt thereof.
  • the device is a three barrel syringe for mixing three solutions, the first solution including an ammonium salt or an amine or a salt thereof, the second solution including hypobromous acid, or a salt thereof, and the third solution including hypochlorous acid, or a salt thereof.
  • the invention features a device for delivery of an N- chlorinated amine including: a) a first reservoir for containing at least one amine source; b) a second reservoir for containing hypochlorous acid or a salt thereof; c) a first conduit connecting the first reservoir to a delivery port; and d) a second conduit connecting the second reservoir to the delivery port.
  • the invention further features a device for delivery of an N-brominated amine including: a) a first reservoir for containing at least one amine source; b) a second reservoir for containing hypobromous acid or a salt thereof; c) a first conduit connecting the first reservoir to a delivery port; and d) a second conduit connecting the second reservoir to the delivery port.
  • the invention also features a device for delivery of a mixture of an N- chlorinated amine and an N-brominated amine including: a) a first reservoir for containing at least one amine source; b) a second reservoir for containing (i) hypobromous acid, or a salt thereof, and (ii) hypochlorous acid, or a salt thereof; c) a first conduit connecting the first reservoir to a delivery port; and d) a second conduit connecting the second reservoir to the delivery port.
  • the device is a three reservoir device for mixing three solutions, the first solution including an ammonium salt or an amine or a salt thereof, the second solution including hypobromous acid, or a salt thereof, and the third solution including hypochlorous acid, or a salt thereof.
  • the device further includes a mechanism to control the flow from the first and second reservoirs through the first and second conduits to the delivery point.
  • the delivery port may be a catheter, a needle, or a spray nozzle.
  • the output is a stream or a mist.
  • the amine is selected from ammonia, urea, methylamine, ethylamine, isobutylamine, 2-methylbutylamine, pyrrolidine, phenethylamine, agmatine, histamine, tryptamine, 3-methylthiopropanamine, spermine, carnosine, carcinine, glutathione sulfonamide, glycine, sulfamic acid, sarcosine, alpha-aminoisobutyric acid, taurine, taurine ethyl ester, taurine sulfonamide, 2-aminoethanol, acetylglycine, alanine, beta-alanine, serine, phenyl alanine, norvaline, leucine, isoleucine, proline, hydroxyproline, omega aminoundecanoic acid, aspartic acid, glutamic acid, asparagine, valine, threonine, cystine
  • 2-amino-5-phosphonopentanoic acid aminoethylphosponic acid, 1 -amino- 1-methylethane phosphonic acid, 1 -amino-2-methylethane phosphonic acid, l-amino-2-methylpropane phosphonic acid, leucine phosphonic acid, 4-amino-4-phosphonobutyric acid, 2-amino-5- phosphonovaleric acid, 2-amino-5-phosphonovaleric acid, 2-amino-8- phosphonooctanoic acid, leucine boronic acid, ⁇ -alanine boronic acid, and salts thereof.
  • the amine is any amine described herein.
  • the amine is taurine, 2,2-dimethyltaurine, 1,1,2,2- tetramethyltaurine, or 2-methyltaurine.
  • one or more of the solutions includes a buffer and has a pH of between 7 and 10.
  • the solution can include a buffer and have a pH of between 7.5 and 10, 7.5 and 9, 7.8 and 10, 7.8 and 9, 7.8 and 8.6, or 8 and 9.
  • the solution formed by mixing the components (e.g., solutions and/or solids) of the device result in a solution having a ratio of unhalogenated amine to halogenated amine that is greater than 1.5 (e.g., a ratio from 1.5 to 20, 2 to 20, 2 to 15, 3 to 20, or 4 to 20).
  • the solution formed by mixing the components (e.g., solutions and/or solids) of the device result in a solution having a concentration of halogenated amine that is between 0.0001 M and 0.25 M (e.g., between 0.001 M and 0.25 M, 0.001 M and 0.125 M, 0.001 and 0.075 M, 0.001 M and 0.025 M, 0.0001 M and 0.05 M, 0.0001 M and 0.025 M, 0.0001 M and 0.010 M, 0.0005 M and 0.025 M, or 0.0005 M and 0.015 M).
  • 0.0001 M and 0.25 M e.g., between 0.001 M and 0.25 M, 0.001 M and 0.125 M, 0.001 and 0.075 M, 0.001 M and 0.025 M, 0.0001 M and 0.05 M, 0.0001 M and 0.025 M, 0.0001 M and 0.010 M, 0.0005 M and 0.025 M, or 0.0005 M and 0.015 M.
  • the invention features a method of treating pain in a patient in need thereof, the method including (i) mixing a solid ammonia salt and a solid hypochlorite salt with water to form an N-chlorinated amine solution, and (ii) administering the solution to a patient for the treatment of pain or itch.
  • the invention further features a method of treating pain in a patient in need thereof, the method including (i) mixing a solid amine salt and a solid hypobromite salt with water to form an N-brominated amine solution, and (ii) administering the solution to a patient for the treatment of pain or itch.
  • the invention further features a method of treating pain in a patient in need thereof, the method including (i) mixing (a) a solid amine salt, (b) a solid hypobromite salt, and (c) a solid hypochlorite salt with water to form a solution containing N-brominated amine and N-chlorinated amine, and (ii) administering the solution to a patient for the treatment of pain or itch.
  • the patient suffers from pain caused by trauma, surgery, herniation of an intervertebral disk, spinal cord injury, shingles, HIV/ AIDS, cancer related pain, amputation, neurodegenerative disorders, carpal tunnel syndrome, diabetic neuropathy, postherpetic neuralgia, fibromyalgia, or a musculoskeletal disorder.
  • the amine salt is salt of ammonia, urea, methylamine, ethylamine, isobutylamine, 2-methylbutylamine.
  • pyrrolidine phenethylamine, agmatine, histamine, tryptamine, 3- methylthiopropanamine, spermine, carnosine, carcinine, glutathione sulfonamide, glycine, sulfamic acid, sarcosine, alpha-aminoisobutyric acid, taurine, taurine ethyl ester, taurine sulfonamide, 2-aminoethanol, acetylglycine, alanine, beta-alanine, serine, phenyl alanine, norvaline, leucine, isoleucine, proline, hydroxyproline, omega aminoundecanoic acid, aspartic acid, glutamic acid, asparagine, valine, threon
  • the solution includes a buffer and has a pH of between 7 and 10.
  • the solution can be buffered and have a pH of between 7 and 9, 7.5 and 10, 7.5 and 9, 7.8 and 10, 7.8 and 9, 7.8 and 8.6, or 8 and 9.
  • the solution has a ratio of unhalogenated amine to halogenated amine that is greater than 1.5 (e.g., a ratio from 1.5 to 20, 2 to 20, 2 to 15, 3 to 20, or 4 to 20).
  • the solution has a concentration of halogenated amine that is between 0.0001 M and 0.25 M (e.g., between 0.001 M and 0.25 M, 0.001 M and 0.125 M, 0.001 and 0.075 M, 0.001 M and 0.025 M, 0.0001 M and 0.05 M, 0.0001 M and 0.025 M, 0.0001 M and 0.010 M, 0.0005 M and 0.025 M, or 0.0005 M and 0.015 M).
  • the invention features a kit including (i) a device of the invention for producing a solution (e.g., an N-brominated amine solution, an N-chlorinated amine solution, or a mixture thereof), and (ii) instructions for administering the solution to a patient for the treatment of pain or itch.
  • a solution e.g., an N-brominated amine solution, an N-chlorinated amine solution, or a mixture thereof
  • instructions for administering the solution to a patient for the treatment of pain or itch.
  • the invention further features a kit including (i) an amine salt, (ii) a hypochlorite salt, and (iii) instructions for contacting the amine salt, and the hypochlorite salt with water to form a solution, and (iv) instructions for administering the solution to a patient for the treatment of pain or itch.
  • the invention also features a kit including (i) an amine salt, (ii) a hypobromite salt, and (iii) instructions for contacting the amine salt, and the hypobromite salt with water to form a solution, and (iv) instructions for administering the solution to a patient for the treatment of pain or itch.
  • the invention further features a kit including (i) an amine salt, (ii) a hypobromite salt, (iii) a hypochlorite salt, and (iv) instructions for contacting the amine salt, the hypobromite salt, and the hypochlorite salt with water to form a solution, and (v) instructions for administering the solution to a patient for the treatment of pain or itch.
  • the invention features a kit including (i) a solid including an N- chlorinated amine, (ii) instructions for contacting the solid with water to form a solution, and (iii) instructions for administering the solution to a patient for the treatment of pain or itch.
  • the N-chlorinated amine is N-chloro-taurine, N-chloro-2,2-dimethyltaurine, N-chloro- 1 , 1 ,2,2- tetramethyltaurine, N-chloro-2,2,3,3-tetramethyl- ⁇ -alanine, N-chloro-3,3- dimethylhomotaurine, N,N-dichloro- taurine, N,N-dichloro-2,2-dimethyltaurine, N,N-dichloro-l,l,2,2-tetramethyltaurine, N,N-dichloro-2,2,3,3-tetramethyl- ⁇ - alanine, N,N-dichloro-3,3-dimethylhomotaurine, or a salt thereof, or any other N-chlorinated amine described herein.
  • the invention also features a kit including (i) a solid including an N- brominated amine, (ii) instructions for contacting the solid with water to form a solution, and (iii) instructions for administering the solution to a patient for the treatment of pain or itch.
  • the N-brominated amine is N-bromo-taurine, N N-bromo-2,2-dimethyltaurine, N-bromo- 1 , 1 ,2,2- tetramethyltaurinc, N-bromo-2,2,3,3-tetramethyl- ⁇ -alanine, N-bromo-3,3- dimethylhomotaurine, N,N-dibromo-taurine, N,N-dibromo-2,2- dimethyltaurine, N,N-dibromo-l , 1 ,2,2-tetramethyltaurine, N,N-dibromo- 2,2,3, 3 -tetramethyl- ⁇ - alanine, N,N-dibromo-3,3-dimethylhomotaurine, or a salt thereof, or any other N-brominated amine described herein.
  • the invention further features a kit including (i) a solid including a halogenated amine selected from N-brominated amines, N-chlorinated amines, N-bromo-N-chloroamines, and mixtures thereof, (ii) instructions for contacting the solid with water to form a solution, and (iii) instructions for administering the solution to a patient for the treatment of pain or itch.
  • a kit including (i) a solid including a halogenated amine selected from N-brominated amines, N-chlorinated amines, N-bromo-N-chloroamines, and mixtures thereof, (ii) instructions for contacting the solid with water to form a solution, and (iii) instructions for administering the solution to a patient for the treatment of pain or itch.
  • the halogenated amine is selected from N-bromo-taurine, N N- bromo-2,2-dimethyltaurine, N-bromo- 1 , 1 ,2,2-tetramethyltaurine, N-bromo- 2,2,3, 3-tetramethyl- ⁇ -alanine, N-bromo-3,3-dimethylhomotaurine, N,N- dibromo-taurine, N,N-dibromo-2,2-dimethyltaurine, N,N-dibromo- 1 , 1 ,2,2- tetramethyltaurine, N,N-dibromo-2,2,3,3-tetramethyl- ⁇ -alanine, N,N-dibromo- 3,3-dimethylhomotaurine, N-chloro-taurine, N-chloro-2,2-dimethyltaurine, N- chloro-l,l,2,2-tetramethyltaurine, N-
  • the solution further includes a buffer in an amount sufficient to produce upon mixing a pH of between 7 and 10.
  • the solution can be buffered to produce a pH of between 7 and 9, 7.5 and 10, 7.5 and 9, 7.8 and 10, 7.8 and 9, 7.8 and 8.6, or 8 and 9.
  • the components are present in amounts to produce upon mixing a solution having a ratio of unhalogenated amine to halogenated amine that is greater than 1.5 (e.g., a ratio from 1.5 to 20, 2 to 20, 2 to 15, 3 to 20, or 4 to 20).
  • the components are present in amounts to produce upon mixing a solution having a concentration of halogenated amine that is between 0.0001 M and 0.25 M (e.g., between 0.001 M and 0.25 M, 0.001 M and 0.125 M, 0.001 and 0.075 M, 0.001 M and 0.025 M, 0.0001 M and 0.05 M, 0.0001 M and 0.025 M, 0.0001 M and 0.010 M, 0.0005 M and 0.025 M, or 0.0005 M and 0.015 M).
  • a concentration of halogenated amine that is between 0.0001 M and 0.25 M (e.g., between 0.001 M and 0.25 M, 0.001 M and 0.125 M, 0.001 and 0.075 M, 0.001 M and 0.025 M, 0.0001 M and 0.05 M, 0.0001 M and 0.025 M, 0.0001 M and 0.010 M, 0.0005 M and 0.025 M, or 0.0005 M and 0.015 M).
  • kits of the invention further include instructions for administering the composition to a patient suffering from pain caused by trauma, surgery, herniation of an intervertebral disk, spinal cord injury, shingles, HIV/AIDS, cancer related pain, amputation, neurodegenerative disorders, carpal tunnel syndrome, diabetic neuropathy, postherpetic neuralgia, fibromyalgia, or a musculoskeletal disorder.
  • the invention features a method of treating pain in a patient in need thereof by topically administering to the patient an agent selected from N- bromoamines and N,N-dibromoamines in an amount sufficient to treat the pain.
  • the invention also features a method of treating pain in a patient in need thereof by topically administering to the patient an N-bromo-N-chloroamine in an amount sufficient to treat the pain.
  • the N-bromo-N- chloroamine is selected from N-bromo-N-chloro-taurine, N-bromo-N-chloro- 2,2-dimethyltaurine, N-bromo-N-chloro- 1 , 1 ,2,2-tetramethyltaurine, N-bromo- N-chloro-2,2,3,3-tetramethyl- ⁇ -alanine, and N-bromo-N-chloro-3,3- dimethylhomotaurine, or a salt thereof.
  • the invention further features a method of treating pain in a patient in need thereof by topically administering to the patient a mixture of (i) a first agent selected from N-chloroamines and N,N-dichloroamines, and (ii) a second agent selected from N-bromoamines and N,N-dibromo-amines, wherein the first agent and the second agent are administered in an amount that together is sufficient to treat the pain.
  • the invention also features a method of treating pain at a site in a patient in need thereof by locally injecting at the site an agent selected from N- bromoamines and N,N-dibromoamines in an amount sufficient to treat the pain.
  • the invention also features a method of treating pain at a site in a patient in need thereof by locally injecting at the site an N-bromo-N-chloroamine in an amount sufficient to treat the pain.
  • the N-bromo-N- chloroamine is selected from N-bromo-N-chloro-taurine, N-bromo-N-chloro- 2,2-dimethyltaurine, N-bromo-N-chloro- 1, 1 ,2,2-tetramethyltaurine, N-bromo- N-chloro-2,2,3,3-tetramethyl- ⁇ -alanine, and N-bromo-N-chloro-3,3- dimethylhomotaurine, or a salt thereof.
  • the invention also features a method of treating pain at a site in a patient in need thereof by locally injecting at the site a mixture of (i) a first agent selected from N-chloroamines and N,N-dichloroamines, and (ii) a second agent selected from N-bromoamines and N,N-dibromo-amines, wherein the first agent and the second agent are administered in an amount that together is sufficient to treat the pain.
  • the invention further features a method of treating pain in a patient in need thereof by administering to the patient an agent selected from N- bromoamines and N,N-dibromoamines in an amount sufficient to treat the pain, wherein the pain is nociceptive pain, somatic pain, visceral pain, procedural pain, or inflammatory pain caused by trauma, surgery, or an autoimmune disease.
  • the invention further features a method of treating pain in a patient in need thereof by administering to the patient an N-bromo-N-chloroamine in an amount sufficient to treat the pain, wherein the pain is nociceptive pain, somatic pain, visceral pain, procedural pain, or inflammatory pain caused by trauma, surgery, or an autoimmune disease.
  • the N- bromo-N-chloroamine is selected from N-bromo-N-chloro-taurine, N-bromo- N-chloro-2,2-dimethyltaurine, N-bromo-N-chloro- 1 , 1 ,2,2-tetramethyltaurine, N-bromo-N-chloro-2,2,3,3-tetramethyl- ⁇ -alanine, and N-bromo-N-chloro-3,3- dimethylhomotaurine, or a salt thereof.
  • the invention further features a method of treating pain in a patient in need thereof by administering to the patient a mixture of (i) a first agent selected from N-chloroamines and N,N-dichloroamines, and (ii) a second agent selected from N-bromoamines and N,N-dibromo-amines, wherein the first agent and the second agent are administered in an amount that together is sufficient to treat the pain, and wherein the pain is nociceptive pain, somatic pain, visceral pain, procedural pain, or inflammatory pain caused by trauma, surgery, or an autoimmune disease.
  • the pain is caused by trauma, surgery, herniation of an intervertebral disk, spinal cord injury, shingles, HIV/AIDS, cancer related pain, amputation, neurodegenerative disorders, carpal tunnel syndrome, diabetic neuropathy, postherpetic neuralgia, fibromyalgia, a musculoskeletal disorder, or any other painful condition described herein.
  • the invention features a method of treating itch in a patient in need thereof by topically administering to the patient an agent selected from N-bromoamines and N,N-dibromoamines in an amount sufficient to treat the itch.
  • the invention features a method of treating itch in a patient in need thereof by topically administering to the patient an N-bromo-N- chloroamine in an amount sufficient to treat the itch.
  • the N-bromo-N-chloroamine is selected from N-bromo-N-chloro-taurine, N- bromo-N-chloro-2,2-dimethyltaurine, N-bromo-N-chloro- 1 , 1 ,2,2- tetramethyltaurine, N-bromo-N-chloro-2,2,3,3-tetramethyl- ⁇ -alanine, and N- bromo-N-chloro-3,3-dimethylhomotaurine, or a salt thereof.
  • the invention features a method of treating itch in a patient in need thereof by topically administering to the patient a mixture of (i) a first agent selected from N-chloroamines and N,N-dichloroamines, and (ii) a second agent selected from N-bromoamines and N,N-dibromo-amines, wherein the first agent and the second agent are administered in an amount that together is sufficient to treat the itch.
  • the agent is administered locally at the site of pain or itch.
  • the invention features a kit including (i) a composition including (a) an agent selected from N-bromoamines and N,N- dibromoamines, (b) an N-bromo-N-chloroamine, or (c) a mixture of a N- chlorinated amine and N-brominated amine in an amount sufficient to treat pain when administered to a patient, and (ii) instructions for topically administering the composition to a patient for the treatment of pain.
  • the composition is formulated for topical administration (e.g., formulated as a cream, lotion, spray, stick, iontophoresis solution, or ointment).
  • the invention also features a kit including (i) a composition formulated for injection and including (a) an agent selected from N-bromoamines and N,N-dibromoamines, (b) an N-bromo-N-chloroamine, or (c) a mixture of a N- chlorinated amine and N-brominated amine in an amount sufficient to treat pain when administered to a patient, and (ii) instructions for locally injecting the composition at a site of a patient for the treatment of pain.
  • a composition formulated for injection and including (a) an agent selected from N-bromoamines and N,N-dibromoamines, (b) an N-bromo-N-chloroamine, or (c) a mixture of a N- chlorinated amine and N-brominated amine
  • the invention further features a kit including (i) a composition including (a) an agent selected from N-bromoamines and N.N-dibromoamines, (b) an N- bromo-N-chloroamine, or (c) a mixture of a N-chlorinated amine and N- brominated amine in an amount sufficient to treat pain when administered to a patient, and (ii) instructions for administering the composition to a patient for the treatment of nociceptive pain, somatic pain, visceral pain, procedural pain, or inflammatory pain caused by trauma, surgery, or an autoimmune disease.
  • a composition including (a) an agent selected from N-bromoamines and N.N-dibromoamines, (b) an N- bromo-N-chloroamine, or (c) a mixture of a N-chlorinated amine and N- brominated amine in an amount sufficient to treat pain when administered to a patient, and (ii) instructions for administering the composition
  • the kit further includes instructions for administering the composition to a patient suffering from pain caused by trauma, surgery, herniation of an intervertebral disk, spinal cord injury, shingles, HIV/ AIDS, cancer related pain, amputation, neurodegenerative disorders, carpal tunnel syndrome, diabetic neuropathy, postherpetic neuralgia, fibromyalgia, a musculoskeletal disorder, or any other painful condition described herein.
  • the invention also features a kit including (i) a composition including (a) an agent selected from N-bromoamines and N,N-dibromoamines, (b) an N- bromo-N-chloroamine, or (c) a mixture of a N-chlorinated amine and N- brominated amine in an amount sufficient to treat itch when administered to a patient, and (ii) instructions for topically administering the composition to a patient for the treatment of itch.
  • a composition including (a) an agent selected from N-bromoamines and N,N-dibromoamines, (b) an N- bromo-N-chloroamine, or (c) a mixture of a N-chlorinated amine and N- brominated amine in an amount sufficient to treat itch when administered to a patient, and (ii) instructions for topically administering the composition to a patient for the treatment of itch.
  • the invention features a kit including (i) an inorganic oxide, (ii) an ammonium salt, (iii) a hypobromite salt, (iv) instructions for contacting the inorganic oxide, the ammonium salt, and the hypobromite salt with water to form a solution, and (v) instructions for administering the solution to a patient for the treatment of pain or itch.
  • the kit further includes a buffer.
  • the kit includes instructions for topically administering the solution into a patient for the treatment of pain or itch or instructions for infusing the solution into a patient at a site of pain.
  • the invention features a kit including (i) an inorganic oxide, (ii) an ammonium salt, (iii) a hypobromite salt, (iv) a hypochlorite salt, and (v) instructions for contacting the inorganic oxide, the ammonium salt, the hypobromite salt, and the hypochlorite salt with water to form a solution, and (v) instructions for administering the solution to a patient for the treatment of pain or itch.
  • the kit further includes a buffer.
  • the kit includes instructions for topically administering the solution into a patient for the treatment of pain or itch or instructions for infusing the solution into a patient at a site of pain.
  • the invention features a bandage including an N-bromo-N-chloroamine in an amount sufficient to treat pain or itch when applied to the skin of a patient.
  • the invention also features a bandage including a mixture of (i) a first agent selected from N-chloroamines and N,N-dichloroamines, and (ii) a second agent selected from N-bromoamines and N,N-dibromo-amines, wherein the first agent and the second agent are present in an amount sufficient to treat pain or itch when applied to the skin of a patient.
  • the invention further features a bandage including an agent selected from N-bromoamines and N,N-dibromoamines in an amount sufficient to treat pain or itch when applied to the skin of a patient.
  • the invention features an infusion device including: (i) a first reservoir containing a first solution including an ammonium salt or an amine or a salt thereof; (ii) a second reservoir containing a second solution including hypobromous acid or a salt thereof; (iii) a mixing chamber for combining the first solution and the second solution to form an N-brominated amine; and (iv) a cannula in fluid communication with the mixer chamber for delivering the N-bromoamine to a subject.
  • the invention features an infusion device including: (i) a first reservoir containing a first solution including an ammonium salt or an amine or a salt thereof; (ii) a second reservoir containing a second solution including hypobromous acid, or a salt thereof, and hypochlorous acid, or a salt thereof; (iii) a mixing chamber for combining the first solution and the second solution to form solution containing N- halogenated amine; and (iv) a cannula in fluid communication with the mixer chamber for delivering the N-halogenated amine to a subject.
  • the invention further features an infusion device including: (i) a reservoir containing a first solution including an ammonium bromide salt and/or an amine and bromide ion; (ii) a power source electrically connected to an electrode in contact with the solution and configured to produce N- bromoamine via electrolysis; and (iii) a cannula in fluid communication with the solution for delivering the N-bromoamine to a subject.
  • the invention features an infusion device including: (i) a reservoir containing a first solution including (a) an ammonium salt, bromide ions, and chloride ions; (ii) a power source electrically connected to an electrode in contact with the solution and configured to produce N-bromoamine, N- chloroamine, and/or N-bromo-N-chloroamine, via electrolysis; and (iii) a cannula in fluid communication with the solution for delivering the solution to a subject.
  • the invention also features an infusion device including: (i) a first reservoir containing a first solution including an amine or a salt thereof; (ii) a second reservoir containing a second solution including bromide ions; (iii) a power source electrically connected to an electrode in contact with the second solution and configured to produce hypobromous acid or a salt thereof via electrolysis; (iv) a mixing chamber for combining the first solution and the hypobromous acid or a salt thereof to form an N-bromoamine; and (v) a cannula in fluid communication with the mixing chamber for delivering the N- bromoamine to a subject.
  • the invention further features an infusion device including: (i) a first reservoir containing a first solution including an amine or a salt thereof; (ii) a second reservoir containing a second solution containing chloride and bromide ions; (iii) a power source electrically connected to an electrode in contact with the second solution and configured to produce both hypochlorous acid, or a salt thereof, and hypobromous acid, or a salt thereof, via electrolysis; (iv) a mixing chamber for combining the first solution and the second solution to form an N- halogenated amine; and (v) a cannula in fluid communication with the mixing chamber for delivering the solution containing the N-halogenated amine to a subject.
  • the ratio of the concentrations of the chloride ions to to the bromide ions is greater than about 1, more preferably it is greater than about 10 and most preferably it equals or exceeds about 100.
  • kits, devices, or bandages the patient experiences some pain relief or some itch relief within 5, 10, 15, 20, 30, or 45 minutes of administering the N-halogenated amine of the invention.
  • kits, devices, or bandages the pain or itch does not result from an infection in the patient.
  • the agent is selected from bromourea, N-bromo-methyl amine, N- bromo-ethylamine, N-bromo-isobutylamine, N-bromo-2-methylbutylamine, N- bromo-pyrrolidine, N-bromo-phenethylamine, N-bromo-agmatine, N-bromo- histamine, N-bromo-tryptamine, N-bromo-3-methylthiopropanamine, N- bromo- spermine, N-bromo-carnosine, N-bromo-carcinine, N-bromo- glutathione sulfonamide, N-bromoglycine, N-bromosulfamic acid, N- bromosarcosine, N-bromo-alpha-aminoisobutyric acid, N-bromotaurine, N- bromotaurine eth
  • the agent is an N-bromo-N-chloroamine selected from N-bromo- N-chloro-methylamine, N-bromo-N-chloro-ethylamine, N-bromo-N-chloro- isobutylamine, N-bromo-N-chloro-2-methylbutylamine, N-bromo-N-chloro- phenethylamine, N-bromo-N-chloro-agmatine, N-bromo-N-chloro-histamine, N-bromo-N-chloro-S-methylthiopropanamine, N-bromo-N-chloro-spermine, N-bromo-N-chloro-carnosine, N-bromo-N- chloro-carcinine, N-bromo-N-chloroglycine, N-bromo-N-chloro
  • the agent is a brominated analgesic, brominated tricyclic antidepressant, brominated stimulant, or a polymer bearing N-bromoamine groups.
  • Brominated analgesics which can be used in the methods, kits, devices, and bandages of the invention include, without limitation, N-bromo-lidocaine, desethyl-N-bromo-lidocaine, N-bromo-prilocaine, N-bromo-tocainide, desethyl-N-bromo-etidocaine, desbutyl-N-bromo-ropivacaine, desbutyl-N- bromo-bupivacaine, desbutyl-N-bromo-levobupivacaine, desmethyl-N-bromo- mepivacaine, desethyl-N-bromo-procaine, desethyl-N-bromo-
  • Brominated tricyclic antidepressants which can be used in the methods, kits, devices, and bandages of the invention include, without limitation, N- bromo-amoxapine, desmethyl-N-bromo-trimipramine, desmethyl-N-bromo- dothiepin, desmethyl-N-bromo-doxepin, desmethyl-N-bromo-amitriptyline, N- bromo-protriptyline, N-bromo-desipramine, desmethyl-N-bromo- clomipramine, desmethyl-N-bromo-clozapine, desmethyl-N-bromo-loxapine, N-bromo-nortriptyline, desmethyl-N-bromo-cyclobenzaprine, desmethyl-N- bromo- cyproheptadine, desmethyl-N-bromo-olopatadine, desmethyl-N-bromo- promethazine, desmethyl-N-brom
  • Brominated stimulants which can be used in the methods, kits, devices, and bandages of the invention include, without limitation, N-bromo- amphetamine, N,N-dibromo-amphetamine, and N-bromo-methamphetamine.
  • Polymers bearing N-bromoamine groups which can be used in the methods, kits, devices, and bandages of the invention include, without limitation, N-brominated chitosan, N-brominated deacetylated hyaluronic acid, N-brominated amino-cellulose, and N-brominated poly lysine (alpha or omega).
  • the agent is a mixture of N-brominated agent and N-chlorinate agent, or an N- bromo-N-chloroamine.
  • the agent can be selected from a halogenated analgesic, halogenated tricyclic antidepressant, halogenated stimulant, or a polymer bearing N-halogenated amine groups. Such agents or mixtures of agents bear both N-bromoamine groups and N-chloroamine groups.
  • the agent is selected from N-bromotaurine, N,N-dibromotaurine, N- bromo-N-chlorotaurine, N-bromo-desmethylchlorpromazine, N-bromo- lidocaine, N-bromo-amphetamine, N,N-dibromo-am ⁇ hetamine, N-bromo-N- chloroamphetamine and N-bromo-methamphetamine and from their mixtures with their N-chloro-analogs, exemplified by the mixture of N-bromotaurine with N-chlorotaurine.
  • the N-brominated amine of the invention desirably has a solubility at about 25 0 C of at least about 10 "6 M, 10 "5 M, 10 "4 M, or
  • the N-brominated amine of the invention has a long life (i.e., is highly stable) in comparison to chloramine, which has a half- life on the order of days.
  • sulfonate salts of N-bromotaurine may be desirable to use as such salts can be stored for many months without significant decomposition.
  • the invention features a method of treating pain in a patient in need thereof by topically administering to the patient a compound of formula (I): or a salt thereof, in an amount sufficient to treat the pain.
  • X is - NHCl, -NHBr, -NCl 2 , -NBr 2 , or -NBrCl
  • Y is -COOH, -CONH 2 , -SO 3 H, - SO 2 NH 2 , -P(O)(OH) 2 , or -B(OH) 2
  • Z is selected from -0-,-S-, -OC(O)-, - C(O)O-, -S(O) 2 -, -NR 3 C(O)-, and -C(O)NR 3 - or Z is absent; each of R 1 and R 2 is, independently, selected from CH 3 , CH 2 CH 3 , and CH 2 CH 2 CH 3 , or R 1 and R 2 combine to form
  • the invention also features a method of treating pain at a site in a patient in need thereof by locally injecting at the site a compound of formula (I) in an amount sufficient to treat the pain.
  • the pain is nociceptive pain, somatic pain, visceral pain, procedural pain, or inflammatory pain caused by trauma, surgery, or an autoimmune disease.
  • the pain is caused by trauma, surgery, herniation of an intervertebral disk, spinal cord injury, shingles, HIV/ AIDS, cancer related pain, amputation, neurodegenerative disorders, carpal tunnel syndrome, diabetic neuropathy, postherpetic neuralgia, fibromyalgia, a musculoskeletal disorder, or any other painful condition described herein.
  • the invention features a method of treating itch in a patient in need thereof by topically administering to the patient a compound of formula (I) in an amount sufficient to treat the itch.
  • the agent is administered locally at the site of pain or itch.
  • the invention features a kit including (i) a composition including a compound of formula (I) in an amount sufficient to treat pain when administered to a patient, and (ii) instructions for topically administering the composition to a patient for the treatment of pain.
  • the composition is formulated for topical administration (e.g., formulated as a cream, lotion, spray, stick, iontophoresis solution, or ointment).
  • the invention also features a kit including (i) a composition formulated for injection and including a compound of formula (I) in an amount sufficient to treat pain when administered to a patient, and (ii) instructions for locally injecting the composition at a site of a patient for the treatment of pain.
  • the compound of formula (I) is selected from N-chloro-2,2-dimethyltaurine, N-chloro- 1 , 1 ,2,2-tetramethyltaurine, N- chloro-2,2,3,3-tetramethyl- ⁇ -alanine, N-chloro-3,3-dimethylhomotaurine, N 5 N- dichloro-2,2-dimethyltaurine, N.N-dichloro- 1 , 1 ,2,2-tetramethyltaurine, N,N- dichloro-2,2,3,3-tetramethyl- ⁇ -alanine, N,N-dichloro-3,3- dimethylhomotaurine, N-bromo-2,2-dimethyltaurine, N-bromo- 1 , 1 ,2,2- tetramethyltaurine, N-bromo-2,2,3,3-tetramethyl- ⁇ -alanine, N-bromo-3,3- dimethylhomotaurine, N-bromo
  • the invention features a solution including a mixture of halogenated amine and unhalogcnated amine dissolved in a buffered aquous solution having a pH of between 7 and 10, wherein (i) the halogenated amine is a chlorinated amine or a brominated amine; (ii) the ratio of unhalogenated amine to halogenated amine in the solution is greater than 1.5; and (iii) the concentration of halogenated amine is between 0.0001 M and 0.25 M.
  • the solution has a pH of between 8 and 9.5 (e.g., the solution can have a pH of between 7.5 and 10, 7.5 and 9, 7.8 and 10, 7.8 and 9, 7.8 and 8.6, or 8 and 9).
  • the solution includes a ratio of unhalogenated amine to halogenated amine of between 2 and 10 (e.g., the ration can be between 1.5 and 50, 1.5 and 10, 2 and 50, 2 and 15, 3 and 50, 3 and 20, or 5 and 25).
  • the concentration of halogenated amine in the solution is between 0.0005 M and 0.015 M (e.g., between 0.0001 M and 0.25 M, 0.001 M and 0.25 M, 0.001 M and 0.125 M, 0.001 and 0.075 M, 0.001 M and 0.025 M, 0.0001 M and 0.05 M, 0.0001 M and 0.025 M, 0.0001 M and 0.010 M, 0.0005 M and 0.025 M, or 0.0005 M and 0.015 M).
  • the amine can be selected from taurine, 2,2-dimethyltaurine, 1,1,2,2-tetramethyltaurine, 2,2,3,3-tetramethyl- ⁇ -alanine, 3,3- dimethylhomotaurine, and salts thereof, or any other amine described herein.
  • the invention also features a kit including (i) the above solution of the invention, and (ii) instructions for keeping the solution refrigerated.
  • the invention also features a method of treating pain in a subject by administering to the subject the above solution of the invention in an amount sufficient to treat the pain.
  • the invention also features a method of treating itch in a subject by administering to the subject the above solution of the invention in an amount sufficient to treat the itch.
  • the invention further features a compound of formula (II) , or a salt thereof:
  • X is -NBrCl
  • Y is -COOH, -CONH 2 , -SO 3 H, -SO 2 NH 2 , - P(O)(OH) 2 , or -B(OH) 2
  • Z is selected from -O-,-S-, -OC(O)-, -C(O)O-, -S(O) 2 -, -NR 2 C(O)-, and -C(O)NR a - or Z is absent
  • each of R 1 and R 2 is, independently, selected from H, CH 3 , CH 2 CH 3 , and CH 2 CH 2 CH 3 , or R 1 and R 2 combine to form a carbocyclic ring of 3 to 8 carbon atoms
  • each of R 3 and R 4 is, independently, selected from H, CH 3 , CH 2 CH 3 , and CH 2 CH 2 CH 3
  • R a is selected from H, CH 3 , CH 2 CH 3 , and CH 2 CH 2 CH 3 , and
  • the compound of formula (II) can be selected from N-bromo-N-chloro-taurine, N-bromo-N-chloro-2,2-dimethyltaurine, N- bromo-N-chloro- 1 , 1 ,2,2-tetramethyltaurine, N-bromo-N-chloro-2,2,3 ,3- tetramethyl- ⁇ -alanine, and N-bromo-N-chloro-S ⁇ -dimethylhomotaurine, or a salt thereof, or any N-bromo-N-chloroamine described herein.
  • the compounds can be used in any of the methods and kits of the invention.
  • the invention features a pharmaceutical composition including (i) a brominated amine, (ii) a chlorinated amine, and (iii) a buffered aquous solution having a pH of between 7 and 10, wherein the concentration of brominated amine is between 0.0001 M and 0.25 M and the concentration of chlorinated amine is between 0.0001 M and 0.25 M. ).
  • the concentration of brominated amine and chlorinated amine in the pharmaceutical composition is between 0.0005 M and 0.015 M (e.g., between 0.0001 M and 0.25 M, 0.001 M and 0.25 M, 0.001 M and 0.125 M, 0.001 and 0.075 M, 0.001 M and 0.025 M, 0.0001 M and 0.05 M, 0.0001 M and 0.025 M, 0.0001 M and 0.010 M, 0.0005 M and 0.025 M, or 0.0005 M and 0.015 M).
  • 0.0005 M and 0.015 M e.g., between 0.0001 M and 0.25 M, 0.001 M and 0.25 M, 0.001 M and 0.125 M, 0.001 and 0.075 M, 0.001 M and 0.025 M, 0.0001 M and 0.05 M, 0.0001 M and 0.025 M, 0.0001 M and 0.010 M, 0.0005 M and 0.025 M, or 0.0005 M and 0.015 M.
  • the pharmaceutical composition has a pH of between 8 and 9.5 (e.g., the solution can have a pH of between 7.5 and 10, 7.5 and 9, 7.8 and 10, 7.8 and 9, 7.8 and 8.6, or 8 and 9).
  • the pharmaceutical composition can be formulated for topical administration, formulated for injection, or formulated in any manner described herein.
  • the ratio of chlorinated amine to brominated amine in the pharmaceutical composition is between 100:1 and 1 :100 (e.g., between 10: 1 and 1 : 100, 100:1 and 1 :10, 50:1 and 1 :50, 20:1 and 1 :20, 1 :1 and 1 :20, or 20:1 and 1 :1).
  • the pharmaceutical composition can be used in any of the methods and kits of the invention.
  • the invention features a compound selected from N-chloro-piperidine- 4-sulfonic acid, N-chloro-piperidine-3 -sulfonic acid, N-bromo-piperidine-4- sulfonic acid, and N-bromo-piperidine-3 -sulfonic acid, or a salt thereof.
  • the compounds can be used in any of the methods and kits of the invention.
  • the pain or itch does not result from an infection in the patient.
  • the term "pain" is used herein in the broadest sense and refers to all types of pain, including acute and chronic pain, such as nociceptive pain, e.g. somatic pain and visceral pain; inflammatory pain, dysfunctional pain, idiopathic pain, neuropathic pain, e.g., centrally generated pain and peripherally generated pain, migraine, and cancer pain.
  • nociceptive pain is used to include all pain caused by noxious stimuli that threaten to or actually injure body tissues, including, without limitation, by a cut, bruise, bone fracture, crush injury, and the like. Pain receptors for tissue injury (nociceptors) are located mostly in the skin, musculoskeletal system, or internal organs. The term “nociceptive pain”
  • spontaneous pain is used to refer to pain arising from bone, joint, muscle, skin, or connective tissue. This type of pain is typically well localized.
  • visceral pain is used herein to refer to pain arising from visceral organs, such as the respiratory, gastrointestinal tract and pancreas, the urinary tract and reproductive organs. Visceral pain includes pain caused by tumor involvement of the organ capsule. Another type of visceral pain, which is typically caused by obstruction of hollow viscus, is characterized by intermittent cramping and poorly localized pain. Visceral pain may be associated with inflammation as in cystitis or reflux esophagitis.
  • inflammatory pain includes pain associated with active inflammation that may be caused by trauma, surgery, infection and autoimmune diseases.
  • neurodegenerative pain is used herein to refer to pain originating from abnormal processing of sensory input by the peripheral or central nervous system consequent on a lesion to these systems.
  • procedural pain refers to pain arising from a medical, dental or surgical procedure wherein the procedure is usually planned or associated with acute trauma.
  • itch also known as pruritus
  • itch is used herein in the broadest sense and refers to all types of itching and stinging sensations localized and generalized, acute intermittent and persistent.
  • the itch may be idiopathic, allergic, metabolic, drug-induced, due to liver, kidney disease, or cancer.
  • patient any animal.
  • the patient is a human.
  • Other animals that can be treated using the methods, compositions, and kits of the invention include but are not limited to non-human primates (e.g., monkeys, gorillas, chimpaneees), domesticated animals (e.g., horses, pigs, goats, rabbits, sheep, cattle, llamas), and companion animals (e.g., guinea pigs, rats, mice, lizards, snakes, dogs, cats, fish, hamsters, and birds).
  • non-human primates e.g., monkeys, gorillas, chimpaneees
  • domesticated animals e.g., horses, pigs, goats, rabbits, sheep, cattle, llamas
  • companion animals e.g., guinea pigs, rats, mice, lizards, snakes, dogs, cats, fish, hamsters, and birds.
  • pharmaceutically acceptable salt represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art.
  • the salts can be prepared in situ during the final isolation and purification of the agents of the invention, or separately by reacting the free base function with a suitable organic acid.
  • Representative acid addition salts include but are not limited to acetate, adipate, alginate, aspartate, benzenesulfonate, benzoate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfatc, cthanesulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, 2-hydroxy-ethanesulfonate, isethionate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, mesylate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate
  • alkali or alkaline earth metal salts include but are not limited to sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • the terms "ester” and "amide” refer derivatives of the N- halogenated amines and their mixtures described herein, including carboxylic acid esters and amides and sulfonic acid esters and amides.
  • Such derivatives include, without limitation the methyl, ethyl, isopropyl, propyl, butyl, and hexyl sulfonic acid esters of N-chloro-taurine and N,N-dichloro- taurine; sulfonamides of N-chloro-taurine and N,N-dichloro-taurine (e.g., formed from ammonia, secondary amines, or primary amines); methyl, ethyl, isopropyl, propyl, butyl, and hexyl carboxylic acid esters of amino acids, such as gamma aminobutyric acid; and carboxylic acid amides (e.g., formed from ammonia, secondary amines, or primary amines) of amino acids, such as gamma aminobutyric acid. Methods for making such derivatives are well known in the art.
  • treating pain is meant preventing, reducing, or eliminating the sensation of pain in a subject.
  • the treatment does not necessarily provide therapy for the underlying pathology that is causing the painful sensation.
  • Treatment of pain can be purely symptomatic.
  • treating itch is meant preventing, reducing, or eliminating the sensation of itch in a subject.
  • the treatment does not necessarily provide therapy for the underlying pathology that is causing the itch.
  • Treatment of itch can be purely symptomatic.
  • an amount sufficient is meant an amount of an agent administered in a method of the invention required to prevent, reduce, or eliminate the sensation of pain (nociception) or itch.
  • the effective amount of agent used to practice the present invention for therapeutic treatment of pain or itch varies depending upon the manner of administration, the age, and body weight, of the subject as well as the route of administration and underlying pathology that is causing the pain or itch. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as a "sufficient" amount.
  • muscleculoskeletal disorder is meant an immune system-related disorder of the muscles, ligaments, bones, joints, cartilage, or other connective tissue.
  • musculoskeletal disorders include various forms of arthritis, e.g., osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, and gout.
  • Other musculoskeletal disorders include acquired hyperostosis syndrome, acromegaly, ankylosing spondylitis, Behcet's disease, bone diseases, bursitis, cartilage diseases, chronic fatigue syndrome, compartment syndromes, congenital hypothyroidism, congenital myopathies, dentigerous cyst, dermatomyositis, diffuse idiopathic skeletal hyperostosis, Dupuytren's contracture, eosinophilia-myalgia syndrome, fasciitis, Felty's syndrome, fibromyalgia, hallux valgus, infectious arthritis, joint diseases, Kabuki make-up syndrome, Legg-Perthes disease, lupus, Lyme disease, Melas syndrome, metabolic bone diseases, mitochondrial
  • administration refers to a method of giving a dosage of agent to a patient, where the method is, e.g., topical, oral, nasal, ocular, subcutaneous, intravenous, intraperitoneal, or intramuscular.
  • the preferred method of administration can vary depending on various factors, e.g., the components of the composition being administered, site of the pain or itch, and its severity.
  • injection refers to bolus or infusion delivery of an agent via needle or cannula, for example, subcutaneously, intravenously, intraperitoneally, or intramuscularly.
  • Topical administration refers to application of an agent of the invention to the skin of a subject. Topical administration includes transdermal administration, such as by iontophoresis.
  • local administration or administration “locally” refers to the delivery of an agent at, or adjacent to, the site of pain or itching, or near part of a nerve transmitting the pain or itching-signal.
  • local administration is typically within about 2 cm or less from the affected nerve ending, preferably within less than about 0.5 cm and most preferably within less than about 2 mm from the ending.
  • halogenated amine is a generic term refering to N- chloroamines, N,N-dichloroamines, N-bromoamines, N,N-dibromoamines, N- bromo-N-chloroamines, and/or mixtures thereof (including, e.g., Halo-NR2, HaIo-NHR, N-halogenated amine-bearing polymers, N-halo-amides, N-halo- ureas, and N-halo-sulfonamides).
  • brominated amine is a generic term refering to N-bromoamines, N,N-dibromoamines, N-bromo-N- chloroamines, and/or mixtures thereof.
  • chlorinated amine is a generic term refering to N-chloroamines, N,N-dichloroamines, N-bromo-N- chloroamines, and/or mixtures thereof.
  • N,N- dichloro means that two chlorine atoms are nitrogen-bound to the same nitrogen atom and N,N-dibromo- means that two bromine atoms are nitrogen- bound to the same nitrogen atom, except where the compound has two nitrogens for which the two halogen atoms can be bound either to the same nitrogen atom or to different nitrogen atoms.
  • nitrogens of the listed N,N- dibromoamines and N,N-dichloroamines can be bound to one chlorine atom and one bromine atom instead of two chlorine or two bromine atoms to form mixed N-bromo-N-chloroamines.
  • FIG. 1 diagrammatically illustrates a mechanically driven spray bottle of the present invention.
  • the separate amine and hypochlorite anion and/or hypobromite anion sources are kept in separate compartments, 51 and 52, of the spray bottle.
  • a septum 50 divides one compartment from the other.
  • a single screw top opening straddles the two compartments and a spray nozzle 54 is attached.
  • the spray nozzle 54 includes a trigger 55. Actuating the trigger initially pulls and delivers a precise volume of a first reactant from compartment 51 through delivery conduit 56.
  • Figure 2 diagrammatically illustrates the tip of a two-reservoir system of the invention that includes a mixing chamber.
  • the catheter shown generally as 220, is a dual-lumen type having lumens 222 and 224.
  • An enclosed reaction chamber 226 serves as a mixing reservoir in which the reactants can react prior to delivery to a subject.
  • a reaction chamber port 228 serves as a point from which N-chlorinated amine and/or N-brominated amine exits the device.
  • Figure 3 diagrammatically illustrates a two-reservoir dispenser in the form of a double barrel syringe.
  • the double barrel syringe 507 has a first chamber 507a and a second chamber 507b.
  • both chambers will be of equal volume for case of determining the final mixture of the N-chlorinated amine and/or N-brominated amine, although double barrel syringes with two chambers of unequal volumes can be used as well.
  • multi-chamber syringes may be used for multi-component N-chlorinated amines and/or N- brominated amines.
  • the two chambers 507a and 507b will also preferably contain osmolality-adjusting agents, viscosity-adjusting agents, and/or pH- adjusting agents for both ease and efficiency of mixing and biocompatibility.
  • the first chamber 507a will contain hypochlorous acid, or a salt thereof and/or hypobromous acid, or a salt thereof.
  • the contents of the second chamber 507b will include an amine, or a salt thereof.
  • the plunger 507d of the two-reservoir dispenser 507 is depressed, the contents of the first chamber 507a and the second chamber 507b are forced through a mixing tip 507c where they are mixed to form an N-chlorinated amine and/or N-brominated amine.
  • the syringe optionally includes a needle for injecting the N-chlorinated amine and/or N-brominated amine into a subject.
  • Figure 4 is a graph depicting the average escape latencies for four groups of rats injected with carrageenan, an agent known to sensitize the paw to pain. Prior to the carrageenan injection, one of four solutions was injected in the hind paws near the carrageenan-injected site: (1) saline, up-pointing triangles; (2) 0.1 M taurine, diamonds; (3) 0.01 M N-chlorotaurine; down- pointing triangles; and (4) 0.1 M N-chlorotaurin, solid squares.
  • the rats were hypersensitive to radiant heat from a focused beam of heat.
  • the time interval between the application of the focused heat and the hind paw withdrawal response is defined as the escape latency.
  • the resulting escape latencies were measured every 30 minutes post carrageenan injection.
  • the 0.1 M N-chlorotaurine injection made the paw insensitive to pain.
  • the escape latency at 60 min was about 12 s, similar to or longer than the about 10 sec escape latency in the paw prior to the carrageenan injection.
  • Figure 5 is is a graph depicting the the elimination of pain- hypersensitivity caused by thermal injury. Following thermal injury, the rats were hypersensitive to radiant heat from a focused beam of heat. The time interval between the application of the focused heat and the hind paw withdrawal response is defined as the escape latency.
  • One of four solutions was injected in the hind paws: (1) saline, open squares; (2) 0.1 M N- chlorotaurine, closed cirlces; (3) 0.3 M N-chlorotaurine; up-pointing triangles; and (4) 1 M N-chlorotaurin, solid squares. As is seen in the top part of Figure
  • FIG. 6 is a graph depicting the average escape latencies for four groups of rats injected with carrageenan, an agent known to sensitize the paw to pain.
  • the potency of N-chlorotaurine in eliminating or decreasing the carrageenan-caused pain hypersensensitivity decreases from the nominally 1 M solution of N-chlorotaurine to the nominally 0.3 M solution of N-chlorotaurine to the nominally 0.1 M solution of N-chlorotaurine.
  • Figure 7 is a graph depicting the average escape latencies for four groups of rats injected with carrageenan, an agent known to sensitize the paw to pain.
  • carrageenan an agent known to sensitize the paw to pain.
  • one of three solutions was injected in the hind paws near the carrageenan- injected site: (1) 0.018 M N- bromotaurine, diamonds; (2) 0.06 M N-bromotaurine, down-pointing triangles; and (3) 0.18 M N-bromotaurine; solid squares.
  • the 10 s escape latency for the uninjured paw is increased to about 14 s, for 0.18 M N- bromotaurine, showing that the N-bromotaurine desensitizes the carrageenan injured paw less even relative to the uninjured paw (data not shown).
  • the N-bromotaurine is still reduces carrageenan-injection caused sensitivity to pain and that at 0.018 M concentration N-bromotaurine still has some beneficial effect.
  • Figure 8 is a graph depicting the heat pain thresholds in UV-B light injured skin (Pre-Injured), and in injured skin before (Pre-NCT), and 30min (Post-NCT 30min) and 90min (Post-NCT 90min) after NCT (right column) or placebo (left column) injection as described in Example 4.
  • Experimental UV-B caused inflammation of the skin resulted in marked heat hyperalgesia as indicated by a decrease in heat (-4.2 0 C) pain threshold.
  • NCT but not placebo exerted robust anti-hyperalgesic effects to heat (+2.8 0 C) stimulation 30 minutes after injection.
  • NCT-mediated antihyperalgesic effects were likely present but attenuated for heat stimulation (+0.8 0 C) 90 minutes after injection.
  • Figure 9 is a graph depicting the mechanical pain thresholds in non- UV- B light injured skin (Pre-Injured), and in UV-B light injured skin before (Pre- NCT), and 30min (Post-NCT 30min) and 90min (Post-NCT 90min) after NCT (right column) or placebo (left column) injection as described in Example 4.
  • Experimental inflammation of the skin resulted in marked mechanical hyperalgesia as indicated by a decrease in mechanical (-3Og) pain threshold.
  • NCT but not placebo exerted robust anti-hyperalgesic effects to mechanical (+45g) stimulation 30 minutes after injection.
  • NCT-mediated antihyperalgesic effects were maintained for mechanical stimulation (+45g).
  • N-chlorinated amines such as chloramine
  • N-brominated amines N-bromo-N-chloroamines
  • their mixtures can be used to relieve pain and itch.
  • N-chloroamine is a generic term meaning N-monochloro-compounds (e.g., Cl-NR 2 , Cl-NHR, N-chlorinated amine- bearing polymers, N-chloro-amides, N-chloro-ureas, and N-chloro- sulfonamides).
  • N-dichloroamine is a generic term meaning N 5 N- dichloro-compounds (e.g., Cl 2 -NR).
  • the N-chlorinated amines of this disclosure are oxidants, for example, of glutathione in vivo and are useful for the treatment of pain and itch.
  • the invention can be carried out using chlorinated simple amines, such as ammonia, methylamine, or ethylamine, or amines which in their unchlorinated form have additional therapeutic utility, such as an analgesic (e.g., N-chloro-lidocaine, desethyl-N-chloro-lidocaine, N- chloro-prilocaine, N-chloro-tocainide, desethyl-N-chloro-etidocaine, desbutyl- N-chloro-ropivacaine, desbutyl-N-chloro-bupivacaine, desbutyl-N-chloro- levobupivacaine, desmethyl-N-chloro-mepivacaine, desethyl-N-chloro- pro
  • N-monochloroamines that can be used in the methods, kits, and compositions of the invention include, without limitation, chloramine, chlorourea, N-chloro-methylamine, N-chloro-ethylamine, N-chloro- isobutylamine, N-chloro-2-methylbutylamine, N-chloro-pyrrolidine, N-chloro- phenethyl amine, N-chloro-agmatine, N-chloro-histamine, N-chloro-tryptamine, N-chloro-3-methylthiopropanamine, N-chloro-spermine, N-chloro-carnosine, N-chloro-carcinine, chloramine T, chloramine B, N-chloro-glutathione sulfonamide, N-chloroglycine, N-chlorosulfamic acid, N-chlorosarcosine, N- chloro-alpha-aminois
  • N-chloro-sulfonamides that can be used in the methods, kits, and compositions of the invention include, without limitation, N-chloro- glutathione sulfonamide, Chloramine-B and Chloramine-T.
  • N-chloro- sulfonamides can be used in their un-ionized and anionic forms. When anionic, it can be the free anion, or a salt, such as a Li + , Na + , K + , Ca 2+ , Mg 2+ , or Zn 2+ salt.
  • the methods, kits, and compositions of the invention can include one or more N-chlorinated amine-bearing polymers.
  • Exemplary chlorinated polymers which can be used in the methods, kits, and compositions of the invention include, without limitation, N-chlorinated chitosan, N-chlorinated deacetylated hyaluronic acid, N-chlorinated amino-cellulose, and N-chlorinated polylysine.
  • N-chlorinated amine-bearing polymers can be prepared using methods analogous to those described in U.S. Patent No. 5,773,608, incorporated herein by reference.
  • the methods, kits, and compositions of the invention can include one or more N,N-dichloroamines.
  • Exemplary N-chloroamines that can be used in the methods, kits, and compositions of the invention include, without limitation, dichloramine, N,N-dichloro-methylamine, N,N-dichloro-ethylamine, N 5 N- dichloro-isobutylamine, N,N-dichloro-2-methylbutylamine, N,N-dichloro- phenethylamine, N,N-dichloro-agmatine, N,N-dichloro-histamine, N 5 N- dichloro-tryptamine, N,N-dichloro-3-methylthiopropanamine, N,N-dichloro- spermine, N,N-dichloro-carnosine, N,N-dichloro-carcinine, N 5 N- dichloroglycine, N,N-dichloro
  • the methods, kits, and compositions of the invention can include one or more N-bromo-N-chloroamines.
  • Exemplary N-bromo-N-chloroamines that can be used in the methods, kits, and compositions of the invention include, without limitation, N-bromo-N-chloramine, N-bromo-N-chloro-methylamine, N-bromo-N-chloro-ethylamine, N-bromo-N-chloro-isobutylamine, N-bromo- N-chloro-2-methylbutylamine, N-bromo-N-chloro-phenethylamine, N-bromo- N-chloro-agmatine, N-bromo-N-chloro-histamine, N-bromo-N-chloro- tryptamine, N-bromo-N-chloro-3 -methy lthiopropanamine, N-bromo-N-ch
  • Halogenated amines can be prepared by the reaction of the amine with a halogen source under reaction conditions which lead to the replacement of one or two hydrogen atoms at the amino nitrogen with halogen atoms. Such reactions are known to chemists skilled in the art.
  • the following halogen sources may be used to produce the N,N-dihalo- amines: HOCl or HOBr or their salts (for example, NaOCl, NaOBr, KOBr or KOCl), N-haloarylsulfonamide salts (i.e., N-halo-4-alkylbenzenesulfonamide); N-halo-succinimide, Cl 2 , and related halogenating agents.
  • N-halo- versus N,N-dihalo- derivatives can be controlled by the relative stoichiometry the amine and halogenating agent.
  • N-bromo-N-chloroamines can be prepared, for example, as described in Haag, Werner R. Journal of Inorganic and Nuclear Chemistry 42:1123 ((1980).
  • Chlorinated amines can be prepared by the reaction of the amine with a chlorine source under reaction conditions which lead to the replacement of one or two hydrogen atoms at the amino nitrogen with chlorine atoms. Such reactions are known to chemists skilled in the art.
  • the following chlorine sources may be used to produce the N 5 N- dichloroamines: HOCl or its salts (for example, NaOCl or KOCl), N- chloroarylsulfonamide salts (i.e., N-chloro-4-alkylbenzenesulfonamide); N- chloro-succinimide, Cl 2 , and related chlorinating agents.
  • HOCl or its salts for example, NaOCl or KOCl
  • N- chloroarylsulfonamide salts i.e., N-chloro-4-alkylbenzenesulfonamide
  • N- chloro-succinimide Cl 2
  • related chlorinating agents in a typical reaction, the amine is dissolved
  • N-chloro-versus N,N-dichloro- derivatives can be controlled by the relative stoichiometry the amine and chlorinating agent.
  • the production of N-chloro-versus N,N-dichloro- derivatives can be controlled by the relative stoichiometry the amine and chlorinating agent.
  • the N-brominated amines described herein can be prepared using analogous methods.
  • N-bromoamine is a generic term meaning N-monobromo-compounds (e.g., Br-NR 2 , Br-NHR, N-brominated amine- bearing polymers, N-bromo-amides, N-bromo-ureas, and N-bromo- sulfonamides).
  • N-dibromoamine is a generic term meaning N 5 N- dibromo-compounds (e.g., Br 2 -NR).
  • N-brominated amines of this disclosure are oxidants, for example, of glutathione in vivo and are useful for the treatment of pain and itch.
  • the invention can be carried out using brominated simple amines, such as ammonia, methylamine, or ethylamine, or amines which in their unbrominated form have additional therapeutic utility, such as an analgesic (e.g., N-bromo-lidocaine, desethyl-N-bromo-lidocaine, N- bromo-prilocaine, N-bromo-tocainide, desethyl-N-bromo-etidocaine, desbutyl- N-bromo-ropivacaine, desbutyl-N-bromo-bupivacaine, desbutyl-N-bromo- levobupivacaine, desmethyl-N-bromo-mepivacaine, desethyl-N-bromo- procaine
  • N-bromoamines that can be used in the methods, kits, and compositions of the invention include, without limitation, bromamine, bromourea, N-bromo-methylamine, N-bromo-ethylamine, N-bromo- isobutylamine, N-bromo-2-methylbutylamine, N-bromo-pyrrolidine, N-bromo- phenethylamine, N-bromo-agmatine, N-bromo-histamine, N-bromo- tryptamine, N-bromo-3-methylthiopropanamine, N-bromo-spermine, N-bromo- carnosine, N-bromo-carcinine, N-bromo- glutathione sulfonamide, N- bromoglycine, N-bromosulfamic acid, N-bromosarcosine, N-bromo-alpha- aminoisobutyric acid, N-bromotaurine, N-
  • N-bromo-sulfonamides that can be used in the methods, kits, and compositions of the invention include, without limitation, N-bromo- glutathione sulfonamide.
  • N-bromo-sulfonamides can be used in their unionized and anionic forms. When anionic, it can be the free anion, or a salt, such as a Li + , Na + , K + , Ca 2+ , Mg 2+ , or Zn 2+ salt.
  • the methods, kits, and compositions of the invention can include one or more N-brominated amine-bearing polymers.
  • Exemplary brominated polymers which can be used in the methods, kits, and compositions of the invention include, without limitation, N-brominated chitosan, N-brominated deacetylated hyaluronic acid, N-brominated amino-cellulose, and N-brominated polylysine.
  • N-brominated amine-bearing polymers can be prepared using methods analogous to those described in U.S. Patent No. 5,773,608, incorporated herein by reference.
  • the methods, kits, and compositions of the invention can include one or more N,N-dibromoamines.
  • Exemplary N-bromoamines that can be used in the methods, kits, and compositions of the invention include, without limitation, N,N-dibromo-methyl amine, N,N-dibromo-ethylamine, N,N-dibromo- isobutylamine, N,N-dibromo-2-methylbutylamine, N,N-dibromo- phenethylamine, N,N-dibromo-agmatine, N,N-dibromo-histamine, N,N- dibromo-tryptamine, N,N-dibromo-3 -methylthiopropanamine, N,N-dibromo- spermine, N,N-dibromo-carnosine, N,N-dibromo-carcinine, N 5 N- dibromog
  • the agents of the invention may be administered by any appropriate route for treatment of pain or itch.
  • the administered agents can also be the paired reactive precursors of the N-chloroamines, N,N-dichloroamines, N-bromoamines or N 5 N- dibromoamines.
  • the N-halocompounds are formed in situ, from the precursor pair consisting of the chlorine or bromine source and the amine, the precursors being generally more stable and longer-lived than the N-chloroamines, N 5 N- dichloroamines, N-bromoamines or N,N-dibromoamines.
  • the agents, or their reactive precursor pairs may be administered to humans, domestic pets, livestock, or other animals with a pharmaceutically acceptable diluent, carrier, or excipient, in unit dosage form.
  • Administration may be topical, parenteral, intravenous, intra-arterial, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol, by suppositories, or oral administration.
  • Therapeutic formulations may be in the form of liquid solutions or suspensions; for oral administration, formulations may be in the form of tablets or capsules; and for intranasal formulations, in the form of powders, nasal drops, ear drops, or aerosols.
  • Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes.
  • Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds.
  • Nanoparticulate formulations may be used to control the biodistribution of the compounds.
  • Other potentially useful parenteral delivery systems include ethylene- vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.
  • the concentration of the compound in the formulation will vary depending upon a number of factors, including the dosage of the drug to be administered, and the route of administration.
  • the agents may be optionally administered as a pharmaceutically acceptable salt, such as a non-toxic acid addition salts or metal complexes that are commonly used in the pharmaceutical industry.
  • acid addition salts include organic acids such as acetic, lactic, pamoic, malic, succinic, benzoic, palmitic, suberic, salicylic, tartaric, methanesulfonic, toluenesulfonic, or trifluoroacetic acids or the like; polymeric acids such as carboxymethyl cellulose, or the like; and inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid phosphoric acid, or the like.
  • Metal complexes include zinc, iron, and the like.
  • the compound of formula I has (i) a narrow therapeutic index (e.g., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; generally, the therapeutic index, TI, is defined as the ratio of median lethal dose (LD 50 ) to median effective dose (ED 50 )); (ii) a narrow absorption window in the gastro- intestinal tract; or (iii) a short biological half- life, so that frequent dosing during a day is required in order to sustain the plasma level at a therapeutic level.
  • a narrow therapeutic index e.g., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small
  • the therapeutic index, TI is defined as the ratio of median lethal dose (LD 50 ) to median effective dose (ED 50 )
  • LD 50 median lethal dose
  • ED 50 median effective dose
  • controlled release can be obtained by the appropriate selection of formulation parameters and ingredients, including, e.g., appropriate controlled release compositions and coatings. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes.
  • Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose and sorbitol), lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc).
  • agents can be infused into a patient using an infusion pump system.
  • skin-adhered infusion delivery systems which can be used include, without limitation, the pump systems described in U.S. Patent Nos.
  • OmniPod a small, lightweight self-adhesive insulin pod that the user fills with insulin and wears directly on the body for up to three days and then replaces.
  • the OmniPod delivers precise, personalized doses of insulin into the body through a small subcutaneously inserted flexible cannula.
  • the company also sells a wireless, handheld device that programs the OmniPod with the user's personalized insulin delivery instructions, wirelessly monitors the OmniPod's operation and incorporates a calibration device.
  • the insulin solution typically employed with these devices can be replaced with an agent of the invention to deliver pain relief at the site of infusion.
  • the dose-rate of agent is between about 10 "9 moles per hour and about 10 "4 moles per hour, preferably between about 10 " moles per hour and about 10 " moles per hour.
  • a preferably aqueous solution or a gel including an agent of the invention is applied topically, for example in a dressing.
  • the concentration of the agent in the solution or gel of the dressing is generally higher than about 0.1 mM and less than about 0.1 M. Preferably, it is higher than about 1 mM and is less than about 30 mM.
  • the agent of the invention is gaseous
  • the dressing has a flexible shell that reduces at least tenfold, preferably one hundred fold, the out diffusion of gases other than hydrogen, for example of oxygen, chlorine, or chloramine.
  • the shell can be adhered to the skin at its edges to form an adequately gas-tight seal slowing the leakage of the volatile agent.
  • the shell can be made of a metallized, for example aluminized, plastic; or it can be made of a plastic through which gases permeate slowly, including, for example, polyvinylidene chloride, used in SaranTM wrap to retard evaporation of water and other volatile components of food.
  • the agents of the invention are adsorbed onto dry carrier particles, such as particles of talcum or zinc oxide, for gradual release when applied topically.
  • the weight percentage of the adsorbed agent is at least about 0.01 wt % and is less than about 10 wt %; it is preferably at least about 0.1 wt % and is less than about 2 wt %.
  • the weight percentage of the chemisorbed oxidant is at least about 0.01 wt % and is less than about 10 wt %; it is preferably at least about 0.1 wt % and is less than about 2 wt %.
  • the agents of the invention can also be delivered topically by iontophoresis.
  • Iontophoresis is a needle-free, non-invasive technology for delivering bioactive agents through the skin using a small electric current to apply an electromotive force that transports ions through the stratum corneum, the outermost layer of skin, and into the dermis, the inner layer of skin that is comprised of connective tissue, blood and lymph vessels, sweat glands, hair follicles and an elaborate sensory nerve network.
  • the hypochlorous acid, or a salt thereof, and/or the hypobromous acid, or a salt thereof, can be contained in a first reservoir to be reacted with an amine, or a salt thereof, contained in a second reservoir. Release from the two reservoirs can be controlled in a variety of way s.
  • the two- reservoir system can be a two-reservoir spray bottle or a dual-barrel syringe. These can be sold as kits containing solids (e.g., an ammonium salt or hypochlorite salt) to be reconstituted just prior to use.
  • the kits can include solutions (e.g., hypochlorite solution and ammonium salt solution), which can be used without reconstitution. Rapid reaction of the hypohalous acid, e.g., hypochlorous acid, or a salt thereof, with the amine produces an N- halogenated, e.g., N-chlorinated amine upon mixing.
  • Hypobromous acid and its salts can be conveniently prepared in-situ by reacting a bromide, such as NaBr or KBr with the hypochlorous acid, or its salt, by co-dissolving the two.
  • a bromide such as NaBr or KBr
  • the agent can be prepared just prior to administration.
  • a dry powder including an ammonium salt and hypochlorite salt can be mixed with water to produce an N- chloroamine just prior to use.
  • an ammonium salt and hypobromite salt can be mixed with water to produce an N-bromoamine just prior to use.
  • the methods, compositions, and kits of the invention are useful for treating pain, including clinical pain, namely inflammatory pain, functional pain, nociceptive pain, and neuropathic pain (e.g., peripheral neuropathic pain), whether acute or chronic (e.g., pain lasting for greater than one, two, three, four, or more months).
  • clinical pain namely inflammatory pain, functional pain, nociceptive pain, and neuropathic pain (e.g., peripheral neuropathic pain), whether acute or chronic (e.g., pain lasting for greater than one, two, three, four, or more months).
  • Conditions that may be associated with pain include, for example, soft tissue, joint, bone inflammation and/or damage (e.g., acute trauma, osteoarthritis, or rheumatoid arthritis), myofascial pain syndromes (fibromylagia), headaches (including cluster headache, migraine and tension type headache), neurodegenerative disorders (i.e., particularly those leading to nerve demyelination), stump pain, myocardial infarction, angina, ischemic cardiovascular disease, post-stroke pain, sickle cell anemia, peripheral vascular occlusive disease, cancer, inflammatory conditions of the skin or joints, diabetic neuropathy, and acute tissue damage from surgery or traumatic injury (e.g., lacerations or fractures).
  • soft tissue, joint, bone inflammation and/or damage e.g., acute trauma, osteoarthritis, or rheumatoid arthritis
  • myofascial pain syndromes fibromylagia
  • headaches including cluster headache, migraine and tension type headache
  • neurodegenerative disorders i.e.
  • the present invention is also useful for the treatment, reduction, or prevention of musculo-skeletal pain (after trauma or exercise), neuropathic pain caused by spinal cord injury, tumors, compression, inflammation, dental pain, episiotomy pain, deep and visceral pain (e.g., heart pain, bladder pain, or pelvic organ pain), muscle pain, eye pain, orofacial pain (e.g., odontalgia, trigeminal neuralgia, glossopharyngeal neuralgia), abdominal pain, gynecological pain (e.g., dysmenorrhea and labor pain), pain associated with nerve and root damage due to trauma, compression, inflammation, toxic chemicals, metabolic disorders, hereditary conditions, vasculitis and autoimmune diseases, central nervous system pain, such as pain due to spinal cord or brain stem damage, cerebrovascular accidents, tumors, infections, demyelinating diseases including multiple sclerosis, chronic lower back pain (e.g., ankylosing spondylitis, degenerative disk disease, radi
  • the present invention is also useful for treating pain associated with post-herpetic neuralgia, cancer, cystic fibrosis, HIV, and polymyalgia rheumatica.
  • the methods, compositions, and kits of the invention can be used to treat pain associated with any of a number of conditions, including back and neck pain, cancer pain, gynecological and labor pain, fibromyalgia, arthritis and other rheumatological pains, orthopedic pains, post herpetic neuralgia and other neuropathic pains, sickle cell crises, interstitial cystitis, urethritis and other urological pains, dental pain, headaches, postoperative pain, and procedural pain (i.e., pain associated with injections, draining an abcess, surgery, dental procedures, opthalmic procedures, arthroscopies and use of other medical instrumentation, cosmetic surgical procedures, dermatological procedures, setting fractures, biopsies, and the like).
  • a measurement index may be used.
  • Indices that are useful in the methods, compositions, and kits of the invention for the measurement of pain associated with musculoskeletal, immunoinflammatory and neuropathic disorders include a visual analog scale (VAS), a Likert scale, categorical pain scales, descriptors, the Lequesne index, the WOMAC index, and the AUSCAN index, each of which is well known in the art.
  • VAS visual analog scale
  • categorical pain scales descriptors
  • the Lequesne index the WOMAC index
  • AUSCAN index AUSCAN index
  • a visual analog scale provides a measure of a one-dimensional quantity.
  • a VAS generally utilizes a representation of distance, such as a picture of a line with hash marks drawn at regular distance intervals, e.g., ten 1- cm intervals. For example, a patient can be asked to rank a sensation of pain or itch by choosing the spot on the line that best corresponds to the sensation of pain or itch, where one end of the line corresponds to "no pain” (score of 0 cm) or "no itch” and the other end of the line corresponds to "unbearable pain” or “unbearable itch” (score of 10 cm). This procedure provides a simple and rapid approach to obtaining quantitative information about how the patient is experiencing pain or itch.
  • VAS scales and their use are described, e.g., in U.S. Patent Nos. 6,709,406 and 6,432,937.
  • a Likert scale similarly provides a measure of a one-dimensional quantity.
  • a Likert scale has discrete integer values ranging from a low value (e.g., 0, meaning no pain) to a high value (e.g., 7, meaning extreme pain).
  • a patient experiencing pain is asked to choose a number between the low value and the high value to represent the degree of pain experienced.
  • Likert scales and their use are described, e.g.. in U.S. Patent Nos. 6,623,040 and 6,766,319.
  • the Lequesne index and the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index assess pain, function, and stiffness in the knee and hip of OA patients using self-administered questionnaires. Both knee and hip are encompassed by the WOMAC, whereas there is one Lequesne questionnaire for the knee and a separate one for the hip. These questionnaires are useful because they contain more information content in comparison with VAS or Likert. Both the WOMAC index and the Lequesne index questionnaires have been extensively validated in OA, including in surgical settings (e.g., knee and hip arthroplasty). Their metric characteristics do not differ significantly.
  • the AUSCAN (Australian-Canadian hand arthritis) index employs a valid, reliable, and responsive patient self-reported questionnaire. In one instance, this questionnaire contains 15 questions within three dimensions (Pain, 5 questions; Stiffness, 1 question; and Physical function, 9 questions).
  • An AUSCAN index may utilize, e.g., a Likert or a VAS scale.
  • Indices that are useful in the methods, compositions, and kits of the invention for the measurement of pain include the Pain Descriptor Scale (PDS), the Visual Analog Scale (VAS), the Verbal Descriptor Scales (VDS), the Numeric Pain Intensity Scale (NPTS), the Neuropathic Pain Scale (NPS), the Neuropathic Pain Symptom Inventory (NPSI), the Present Pain Inventory (PPI), the Geriatric Pain Measure (GPM), the McGiIl Pain Questionnaire (MPQ), mean pain intensity (Descriptor Differential Scale), numeric pain scale (NPS) global evaluation score (GES) the Short-Form McGiIl Pain Questionnaire, the Minnesota Multiphasic Personality Inventory, the Pain Profile and Multidimensional Pain Inventory, the Child Heath Questionnaire, and the Child Assessment Questionnaire.
  • PDS Pain Descriptor Scale
  • VAS Visual Analog Scale
  • VDS Verbal Descriptor Scales
  • NPTS Numeric Pain Intensity Scale
  • NPS Neuropathic Pain Scale
  • Sodium bicarbonate (100 mL of 0.1 M NaHCOs) solution was prepared by dissolving 840 mg (0.01 mols) OfNaHCO 3 , MW 84) in 100 mL de-ionized water. The solution was cooled to about 4 "C.
  • Taurine (612 mg, 0.005 mols; ⁇ H 3 CH 2 CH 2 SO 3 " , MW 125) was dissolved in 50 mL of the NaHCO 3 solution.
  • the taurine concentration in the resulting solution is 0.1 M, and the NaHCO 3 concentration is about 0.1M.
  • the solution was maintained at 4 °C.
  • Sodium hypochlorite (about 13 % w/w Cl 2 , about 1.75 M) solution was diluted with the chilled 0.1 M NaHCO 3 solution (2.5 mL of the 1.75 M NaOCl into 50 mL NaHCO 3 solution).
  • the concentration of NaOCl in the resulting solution is about 0.1 M, and the concentration OfNaHCO 3 is about 0.1 M.
  • the chilled NaOCl solution 50 mL, 0.005 mols
  • the chilled taurine solution 50 mL, 0.005 mols
  • the resulting solution contains about 0.043 M N-chlorotaurine in about 0.1 M NaHCO 3 (the solution is about isotonic and very slightly basic, pH about 8.3).
  • This refrigerated N-chlorotaurine stock solution can be used for at least 4 hours. It may be diluted immediately before use with physiological saline phosphate buffer (pH 7.3, 0.14 M NaCl, 0.02 M phosphate) and administered to a subject according to the methods of the invention.
  • physiological saline phosphate buffer pH 7.3, 0.14 M NaCl, 0.02 M phosphate
  • Example 2 Stability of N-chlorotaurine and N-bromotaurine Solutions.
  • concentration of N-chlorotaurine and N- bromotaurine is, at a particular pH, temperature and taurine concentration, given by Equation 1.
  • Equation 1 C 0 is the initial concentration, C t is the concentration at time t, and k is a constant.
  • N-chlorotaurine The half-life of an N-chlorotaurine solution decreases when the N- chlorotaurine concentration is increased.
  • concentration of N-chlorotaurine is conveniently monitored by its absorption of 252 nm UV light, where at neutral or slightly acidic pH its molar absorbance is about 430 cm "1 .
  • An example of the initial N-chlorotaurine concentration effect is shown in Table 1.
  • NCT N-chlorotaurine
  • T taurine
  • NaHCO3 sodium bicarbonate
  • the rate of decay of the N-bromotaurine concentration decreases when its solution is diluted.
  • 24.5 g (ca. 0.21 moles) of KBr were dissolved in 250 mL of a NaOH-stabilized 6.6 % sodium hypochlorite solution with a pH of about 12.
  • a NaOH-stabilized 6.6 % sodium hypochlorite solution with a pH of about 12.
  • concentrated HCl the pH was lowered to about pH 9.
  • the 250 mL volume of this solution contained 0.21 moles of NaOCl.
  • the hypobromite concentration in the resulting solution was about 0.82 M and the hypochlorite concentration was about 0.06 M.
  • the N-bromotaurine solution was made by adding 30 mL of the hypobromite solution to 50 mL of the taurine solution drop-wise with stirring over 20 minutes.
  • the pH increased upon the mixing from 7.3 to about 8.1.
  • the resulting solution was about 0.25 M NBT, about 0.02 M NCT and about 0.14 M taurine.
  • the absorption maximum and the absorbance of the solution was pH dependent. The maximum was downshifted from about 280 nm to about 260 nm as the pH was raised from 7 to 8.5 and there was an about three-fold decrease in the absorbance.
  • the concentration decay was tracked by measuring the decay of the absorbance at 410 nm. The rate of decay was about 0.43 % min "1 .
  • the solution was kept at the ambient temperature of about 21 °C for about 30-40 minutes, and was then diluted with an equal volume of de-ionized water. The pH of the diluted solution was about 8.1.
  • NCT N-chlorotaurine
  • T taurine
  • NaHCO 3 sodium bicarbonate
  • N-chlorotaurine is more stable than dissolved N-bromotaurine.
  • concentration of N-bromotaurine is conveniently monitored by its absorption of 283 nm UV light, where it molar absorbance in neutral or slightly acidic solutions is about 415 cm "1 .
  • Table 3 compares the stabilities of about 0.2M solutions of N-chlorotaurine and N- bromotaurine at about similar pH and about similar taurine excess.
  • NCT is N-chlorotaurine
  • NBT is N-bromotaurine
  • T is taurine
  • the residual concentrations of N-chlorotaurine and of N-bromotaurine were monitored through diluting their solution one hundred fold and measuring their absorbances respectively at about 252 nm and 283 nm. Decay was monitored at an ambient temperature of about 21 0 C.
  • co-dissolved taurine e.g., the addition of 1, 2, 3, 4, or more molar equivalents of the unhalogenated amine
  • solubility of taurine limits its upper concentration to about 1 M at body temperature (about 37 0 C)
  • a taurine concentration of between about 0.3 M and about 1 M is utilized to improve the stability of the halogenated taurine.
  • Table 4 shows that co-dissolved taurine stabilizes the about 0.2 M N-bromotaurine solution.
  • NBT N-bromotaurine
  • T taurine
  • the residual concentration of N-bromotaurine was monitored through diluting their solution one hundred fold and measuring the absorbance at about 283 nm at an ambient temperature of about 21 °C.
  • a solution containing about 0.25 M NBT, about 0.02 M NCT and about 0.55 M taurine was prepared as described above (except the dilution was carried out with 0.825 M taurine solution instead of water).
  • the initial pH of 7.4 was adjusted to the pH of 8.1 by adding solid sodium carbonate.
  • the rate of the decay of the N-bromotaurine concentration decreased to less than l/3 rd of the rate observed for the water-diluted solution (0.05 % min ⁇ l versus 0.17 % min -1 ). Effect of Temperature
  • taurine (5 g, 0.04 moles) was dissolved in 20 mL of dcionized water and the pH of the solution was raised to 8-9 by adding solid sodium bicarbonate. The NaOBr solution was added drop-wise over 15 minutes to the taurine solution, to produce N-bromotaurine (see Reaction 1).
  • the pH of the solution was adjusted to about 8.3 +/- 0.7 by adding NaHCO 3 .
  • the solution was then kept for 1 hour at ambient temperature to allow completion of the reaction.
  • the resulting solution contained about 0.01 moles of N-bromotaurine and about 0.03 moles of taurine; thus the N-bromotaurine concentration was about 0.2 M and the taurine concentration was about 0.6 M.
  • the solution was next diluted with 200 mL water to produce a solution volume of 250 mL.
  • the resulting solution had 0.04 M in N-bromotaurine and 0.12 M taurine concentrations. In a one-week stability test, this solution was unstable, losing most of its UV light absorbance at 283 nm, where the absorbance of N- bromotaurine is maximal.
  • a Hargreaves- type testing device was used (Dirig et al., J. Neurosci. Methods 76:183 (1991)).
  • the device consists of a glass surface (maintained at 30 ° C) on which the rats are placed individually in Plexiglas cubicles.
  • the thermal nociceptive stimulus originates from a focused projection bulb positioned below the glass surface.
  • a timer is activated by the light source, and latency was defined as the time required for the paw to show a brisk withdrawal as detected by photodiode motion sensors that stopped the timer and terminated the stimulus.
  • the thermal stimulator permits the focusing a beam of radiant heat on the plantar surface of the paw, usually the hind paw, through a glass surface on which the animal stands. After a period of time, the paw is heated by the beam to a pain-causing temperature. When the rat feels pain, it withdraws the paw. Usually the rat is placed in a clear plastic cage that rests on an elevated floor of clear glass. An x-y movable focused radiant heat source is located under the glass floor maintained at 3O 0 C. The current to the radiant heat source was controlled by a variable current supply, permitting increase or decrease of the intensity of the radiant heat focused on the paw.
  • the focused radiant heat was aimed on the carrageenan- injected or thermally injured portion of the plantar surface of the hind paw. After about 30 min of acclimation of the rat in the cage, the radiant beam was adjusted so that the average escape latency in normal untreated rats, meaning the time interval between the application of the focused beam of radiant heat and the brisk paw withdrawal, was about 10 sec. The paw withdrawal was detected automatically with a photodetector.
  • the results are shown in Figures 4-7. Intraplantar administration of N- chlorotaurine or N-bromotaurine reverses carrageenan and thermal injury evoked hyperalgesic states in a dose dependent fashion. Furthermore, the N- chlorotaurine and N-bromotaurine had no effect on "normal" (uninjured) pain- thresholds. No untoward effects were observed at the maximum doses/concentration employed.
  • Example 4 Anti-Hyperalgesic Activity of N-chlorotaurine in Human Subjects.
  • General design Two subjects participated in a single study session over the course of two days. On study day one, an experimental sunburn lesion was induced in non-tanned skin on each thigh. On study day two and 22 hours after induction of the experimental sunburn lesions, subjects participated in behavioral pain experiments. Before study participation a subject's sensitivity to UVB irradiation was determined.
  • the minimal erythemal dose (MED; mJ/cm 2 ), i.e.. the minimal energy of UVB causing complete reddening of skin 22 hours after irradiation was determined in each subject in non tanned skin of the upper thigh before study participation. Both subjects had an MED of lOOmJ/cm 2 .
  • Experimental sunburn lesions (1.5x1.5 cm) were induced using close to three times the MED (280mJ/cm ) in non tanned skin of each upper thigh 22 h before the behavioral pain testing. Pain testing
  • Pain thresholds to heat and mechanical stimulation were determined in experimental sunburn lesions and at non-inflamed skin control sites. Pain thresholds are defined as the minimal heat or mechanical stimulus necessary to evoke a painful sensation.
  • the pain threshold was determined with aid of a thermal sensory analyzer (TSA II, Medoc Advanced Medical Systems, Durham, NC).
  • TSA II Medoc Advanced Medical Systems, Durham, NC
  • a hand-held 16x16 mm thermode was brought into full contact with skin. After equilibration between skin and thermode temperature at 35 0 C, the temperature of the thermode was increased by l°C/s (cut-off 52°C). Subject were asked to push the button of a hand-held device as soon as pain was perceived, thereby triggering the recording of the temperature causing pain as well as the immediate cooling of the probe. This procedure was repeated 4 times and the average was recorded.
  • Mechanical hyperalgesia was quantified with eight calibrated punctuated probes.
  • the eight probes are made of identical cylindrical stainless steel wires (240 ⁇ m diameter) mounted on copper rods of various weights (1, 2, 4, 8, 16, 32, 64 and 81 g) moving freely within a wider hand-held tube.
  • Punctuated stimuli were applied by positioning the steel wire tip perpendicular to the skin surface such that the weight of a rod rested solely on the wire tip. Starting with the lightest probe, consecutively heavier probes were applied until a subject reported pain for the first time. Subsequently, the next lighter probe was applied if pain had been reported for the preceding stimulus, or the next hea ⁇ der probe was applied if no pain had been reported for the preceding stimulus.
  • the procedure was repeated until a subject had reported four times that a non- painful stimulation had changed to a painful stimulation and three times that a painful stimulation had changed to a non-painful stimulation, respectively. This way seven data points were obtained reflecting the weight of the probe that caused a change from a non-painful to a painful perception and vice versa.
  • the mechanical pain threshold was defined as the mean of these seven data points.
  • NCT N-Chlorotaurine
  • ⁇ total of 800 ⁇ l of NCT solution or placebo were injected in each lesion via a 27G needle attached to a ImL syringe.
  • the 800 ⁇ l were injected as follows: lOO ⁇ l each were injected intra- cutaneously in each quadrant of the experimental sunburn lesion, and 400 ⁇ l were injected subcutaneously into the center of the lesion.
  • Administration was performed after determining the pre-drug heat and mechanical pain threshold twice. Pain thresholds were reassessed in both lesions 30 and 90min after drug administration.
  • Chlorotaurine was dissolved 5-10 minutes before the injection.
  • the active solution was formulated as follows: 2ml water was added to a vial containing 42mg of NCT-Na salt to obtain a 0.1 M solution. In addition 8.4mg NaHCO 3 were added to provide a final concentration of 0.05M.
  • the placebo solution was formulated as follows: 2ml water was added to a vial containing 25.2mg NaHCO 3 to provide a final concentration of 0.15M.

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Abstract

L’invention concerne des méthodes, des trousses et des compositions pour le traitement de la douleur.
PCT/US2009/053024 2008-08-06 2009-08-06 Méthodes et compositions pour le traitement de la douleur Ceased WO2010017405A1 (fr)

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Cited By (10)

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Publication number Priority date Publication date Assignee Title
CN102526103A (zh) * 2010-12-07 2012-07-04 西藏海思科药业集团股份有限公司 一种多种微量元素注射液及其制备方法
WO2012054521A3 (fr) * 2010-10-19 2012-07-19 Novabay Pharmaceuticals, Inc. Composés polyéther et polyol antimicrobiens
AU2011306407B2 (en) * 2010-09-21 2015-06-11 Bromine Compounds Ltd. Method for preparing bromourea
WO2017149331A1 (fr) * 2016-03-01 2017-09-08 Nasco Ad Biotechnology Laboratory Solutions et émulsions de n-bromotaurine dirigées contre des cellules anormales
US9999605B2 (en) 2012-07-24 2018-06-19 Rls Global Ab Preparation for treatment of a non-oral treatment site comprising an active chlorine compound and amino acids
US20190151459A1 (en) * 2013-01-28 2019-05-23 Hector L. Lopez Methods of improving tolerability, pharmacodynamics, and efficacy of beta-alanine and use therefor
CN110156608A (zh) * 2019-04-24 2019-08-23 深圳市第二人民医院 绿卡色林中间体对氯苯乙胺的合成方法
US10499647B2 (en) 2017-01-10 2019-12-10 Ecolab Usa Inc. Use of an encapsulated chlorine bleach particle to reduce gas evolution during dispensing
WO2023250486A1 (fr) * 2022-06-24 2023-12-28 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Composes d'acides gras
EP4585254A1 (fr) * 2024-01-09 2025-07-16 Heraeus Medical GmbH Solution de rinçage de plaie pour éliminer des biofilms

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US20020065484A1 (en) * 2000-11-29 2002-05-30 Douglas Joel Sterling Dual lumen subcutaneous injection set for use with a reservoir that has a septum
US20040018228A1 (en) * 2000-11-06 2004-01-29 Afmedica, Inc. Compositions and methods for reducing scar tissue formation
US20050221113A1 (en) * 2004-03-23 2005-10-06 Bitowft Bruce K Packagin for dilute hypochlorite
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US3449225A (en) * 1966-02-01 1969-06-10 Monsanto Co Electrolytic processes for preparing halogenated organic compounds
US20040018228A1 (en) * 2000-11-06 2004-01-29 Afmedica, Inc. Compositions and methods for reducing scar tissue formation
US20020065484A1 (en) * 2000-11-29 2002-05-30 Douglas Joel Sterling Dual lumen subcutaneous injection set for use with a reservoir that has a septum
US20050221113A1 (en) * 2004-03-23 2005-10-06 Bitowft Bruce K Packagin for dilute hypochlorite
US20060247209A1 (en) * 2005-01-25 2006-11-02 Ramin Najafi N-halogenated amino acids, N,N-dihalogenated amino acids and derivatives; compositions and methods of using them

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2011306407B2 (en) * 2010-09-21 2015-06-11 Bromine Compounds Ltd. Method for preparing bromourea
WO2012054521A3 (fr) * 2010-10-19 2012-07-19 Novabay Pharmaceuticals, Inc. Composés polyéther et polyol antimicrobiens
JP2013545728A (ja) * 2010-10-19 2013-12-26 ノバベイ・ファーマシューティカルズ・インコーポレイテッド 抗菌性ポリエーテルおよびポリオール化合物
US9248117B2 (en) 2010-10-19 2016-02-02 Novabay Pharmaceuticals, Inc. Substituted N,N-dihaloamines as antimicrobials
CN102526103B (zh) * 2010-12-07 2013-11-13 西藏海思科药业集团股份有限公司 一种多种微量元素注射液药物组合物及其制备方法
CN102526103A (zh) * 2010-12-07 2012-07-04 西藏海思科药业集团股份有限公司 一种多种微量元素注射液及其制备方法
US9999605B2 (en) 2012-07-24 2018-06-19 Rls Global Ab Preparation for treatment of a non-oral treatment site comprising an active chlorine compound and amino acids
US20190151459A1 (en) * 2013-01-28 2019-05-23 Hector L. Lopez Methods of improving tolerability, pharmacodynamics, and efficacy of beta-alanine and use therefor
WO2017149331A1 (fr) * 2016-03-01 2017-09-08 Nasco Ad Biotechnology Laboratory Solutions et émulsions de n-bromotaurine dirigées contre des cellules anormales
US12076303B2 (en) 2016-03-01 2024-09-03 Nasco Ad Biotechnology Laboratory N-bromotaurine solutions and emulsions against abnormal cells
US10499647B2 (en) 2017-01-10 2019-12-10 Ecolab Usa Inc. Use of an encapsulated chlorine bleach particle to reduce gas evolution during dispensing
CN110156608A (zh) * 2019-04-24 2019-08-23 深圳市第二人民医院 绿卡色林中间体对氯苯乙胺的合成方法
CN110156608B (zh) * 2019-04-24 2022-04-01 深圳市第二人民医院 绿卡色林中间体对氯苯乙胺的合成方法
WO2023250486A1 (fr) * 2022-06-24 2023-12-28 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Composes d'acides gras
EP4585254A1 (fr) * 2024-01-09 2025-07-16 Heraeus Medical GmbH Solution de rinçage de plaie pour éliminer des biofilms
WO2025149449A1 (fr) * 2024-01-09 2025-07-17 Heraeus Medical Gmbh Solution de rinçage de plaie permettant d'éliminer un biofilm

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