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Uses and Compositions for Administration of Capsaicin

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(19) TZZ__Z _T (11) EP 1 610 742 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/165 (2006.01) A61K 9/08 (2006.01) 21.01.2015 Bulletin 2015/04 A61K 9/127 (2006.01) A61K 47/08 (2006.01) A61P 23/02 (2006.01) (21) Application number: 04750050.9 (86) International application number: (22) Date of filing: 12.04.2004 PCT/US2004/011336 (87) International publication number: WO 2004/091521 (28.10.2004 Gazette 2004/44) (54) USES AND COMPOSITIONS FOR ADMINISTRATION OF CAPSAICIN VERWENDUNG UND ZUSAMMENSETZUNGEN ZUR VERABREICHUNG VON CAPSAICIN UTILISATION ET COMPOSITIONS POUR L’ADMINISTRATION DE LA CAPSAÏCINE (84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • MUHAMMAD, Naweed HU IE IT LI LU MC NL PL PT RO SE SI SK TR Sacramento, CA 95820 (US) Designated Extension States: • JAMIESON, Gene AL HR LT LV MK Boulder Creek, CA 95006 (US) •BLEY,Keith (30) Priority: 10.04.2003 US 462040 P Mountain View, CA 94043 (US) 10.04.2003 US 462457 P • CHANDA, Sanjay 29.08.2003 US 499062 P South San Francisco, CA 94080 (US) (43) Date of publication of application: (74) Representative: Roques, Sarah Elizabeth 04.01.2006 Bulletin 2006/01 J A Kemp 14 South Square (60) Divisional application: Gray’s Inn 14198000.3 London WC1R 5JJ (GB) (73) Proprietor: Neurogesx, Inc. (56) References cited: San Mateo, CA 94404 (US) WO-A1-2004/089361 WO-A2-02/09763 US-A- 4 892 890 US-A- 5 654 337 US-A- 5 665 378 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 610 742 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 610 742 B1 Description FIELD OF THE INVENTION 5 [0001] The invention relates to compositions and methods for reducing the density of sensory nerve fibers in tissue and amelioration of capsaicin-responsive conditions, and finds application in the field of medicine. BACKGROUND 10 [0002] The transient receptor potential vanilloid-1 (TRPV1) is a capsaicin-responsive ligand-gated cation channel selectively expressed on small, unmyelinated peripheral nerve fibers (cutaneous nociceptors). See Caterina and Julius, 2001, "The vanilloid receptor: a molecular gateway to the pain pathway," Annu Rev Neurosci.24:487-517; and .Montell et al., 2002, "A unified nomenclature for the superfamily of TRP cation channels," Mol. Cell. 9:229-31. When TRPV1 is activated by agonists such as capsaicin and other factors such as heat and acidosis, calcium enters the cell and pain 15 signals are initiated. After disease or injury, cutaneous nociceptors may become persistently hyperactive, spontaneously transmitting excessive pain signals to the spinal cord in the absence of painful stimuli, resulting in various types of chronic pain. When TRPV1 is continuously activated through prolonged exposure to an agoniste.g ( ., capsaicin), excessive calcium enters the nerve fiber, initiating processes that result in long-term yet reversible impairment of nociceptor function. This is believed to be the mechanism by which application of capsaicin provides relief from pain. 20 [0003] Capsaicin may be effective for amelioration of conditions or diseases other than pain, as well. For example, capsaicin acts as an anti-inflammatory agent, counterirritant, antipruritic, anti-psoriatic and anti-itch agent (for review, see Szallasi and Blumberg, 1999, "Vanilloid (Capsaicin) Receptors and Mechanisms," Pharm Revs, 51:159-211). In addition, capsaicin has been reported to cause apoptosis and/or inhibit proliferation of malignant cancer cells (for review, see Surh, 2002, "More Than Spice: Capsaicin in Hot Chili Peppers Makes Tumor Cells Commit Suicide," J Nat Cancer 25 Inst, 94: 1263-65), and to reduce sinonasal polyps (Baudoin et al., 2000, "Capsaicin significantly reduces sinonasal polyps" Acta Otolaryngol 120:307-11). [0004] Low-concentration capsaicin creams have been used for years to treat painful neuropathies and musculoskeletal pain, but their use is limited because they are painful and inconvenient to apply, normally requiring multiple daily appli- cations for only modest relief. Recently, a high concentration capsaicin patch has been developed (NGX-4010; Neuro- 30 gesX, Inc.) that is believed to provide effective and sustained relief from pain. US 5665378 relates to a transdermal therapeutic formulation comprising capsaicin, a nonsteroidal anti-inflammatant and pamabrom. US 5654337 relates to a composition useful in the delivery of pharmaceutically active agents through the skin. [0005] The present invention provides additional methods and compositions for administration of capsaicin and other 35 TRPV1 agonists. BRIEF SUMMARY OF THE INVENTION [0006] The invention relates to compositions for administration of capsaicin, to individuals in need of treatment. Ac- 40 cordingly, the present invention provides the use of capsaicin and a solvent system in the manufacture of a liquid solution for treating a capsaicin-responsive condition in a subject, by non-occlusive or non-adherent administration of said liquid formulation, wherein said solvent system contains two, three, four, five or more than five penetration enhancers, wherein the penetration enhancers comprise: (a) oleyl alcohol and propylene glycol; (b) n-hexane and methylnonenoic acid; or (c) menthone and methanol, wherein said liquid solution delivers at least 3 nmoles of capsaicin to a 1 cm 2 area of skin 45 in 15 minutes as measured in a mouse skin absorption assay, and wherein the capsaicin-responsive condition is neu- ropathic pain, pain produced by mixed nociceptive and neuropathic etiologies, inflammatory hyperalgesia, vulvodynia, interstitial cystitis, overactive bladder, prostatic hyperplasia, rhinitis, rectal hypersensitivity, burning mouth syndrome, oral mucositis, herpes, prostatic hypertrophy, dermatitis, pruritis, itch, tinnitus, psoriasis, warts, skin cancers, headaches, or wrinkles. 50 [0007] Described herein are methods of reducing the density of functional nociceptive nerve fibers in a selected region of a subject by contacting the region with a composition that contains capsaicin and a solvent system by two or more penetration enhancers, where said composition delivers at least about 3 nmoles capsaicin to skin as measured in a mouse skin absorption assay. The composition may be an immediate-release composition. The contacting may be under nonocclusive conditions. The contacting may be under nonadherent conditions. At least about 5 mL of the composition 55 may be delivered to each cm2 of the region in about 15 minutes. A 15 minute application of the composition to skin of a mammal may result in a decrease in the density of functional nociceptive nerve fibers by at least about 20%. The density of functional nociceptive nerve fibers may be decreased by at least about 50%. The mammal may be a mouse. The mammal may be a human. 2 EP 1 610 742 B1 [0008] Described herein are methods of treating a capsaicin-responsive condition in a subject by administration of a composition that contains capsaicin and at least two penetration enhancers, where said composition delivers at least about 3 nmoles capsaicin to skin as measured in a mouse skin absorption assay. The composition may be an immediate release composition. The administration may be non-occlusive and/or non-adherent. The capsaicin-responsive condition 5 is neuropathic pain, pain produced by mixed nociceptive and neuropathic etiologies, inflammatory hyperalgesia, vulvo- dynia, interstitial cystitis, overactive bladder, prostatic hyperplasia, rhinitis, rectal hypersensitivity, burning mouth syn- drome, oral mucositis, herpes, prostatic hypertrophy, dermatitis, pruritis, itch, tinnitus, psoriasis, warts, skin cancers, headaches, or wrinkles. The composition may be applied to an area on the surface of skin or mucosa. [0009] Also described herein are methods of treating a capsaicin-responsive condition in a subject, by administration 10 of a composition that contains capsaicin and at least two penetration enhancers, where said composition delivers at least about 3 nmoles capsaicin to skin as measured in a mouse skin absorption assay. [0010] The composition may deliver at least about 6 nmoles capsaicin to skin, at least about 16 nmoles, at least about 32 nmoles, at least about 49 nmoles, or at least about 65 nmoles capsaicin to skin in a mouse skin absorption assay. [0011] The composition may have a depot effect of less than about 0.25 as measured in a mouse skin absorption 15 assay. The depot effect may be less than about 0.1, less than about 0.02, or less than about 0.001. [0012] The composition may contain the capsaicin and a solvent system, where penetration enhancer(s) make up at least 20% (v/v) of the solvent system. Penetration enhancer(s) may make up at least 50% (v/v), at least 90%, at least 95% or substantially all of the solvent system. The composition may comprise the capsaicin at a concentration of from 0.05% (w/v) to 60% (w/v). 20 [0013] The solvent system may contain a penetration enhancer that is an ether, ester, alcohol, fatty acid, fatty acid ester, fatty alcohol, polyol, terpene, or amine. The solvent system may contain a penetration enhancer selected from 1- menthone, dimethyl isosorbide, caprylic alcohol,
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  • Characterization of Human TRPA1 and TRPV1 Channels in Response to Naturally Occurring Defensive Compounds

    Characterization of Human TRPA1 and TRPV1 Channels in Response to Naturally Occurring Defensive Compounds

    Characterization of human TRPA1 and TRPV1 channels in response to naturally occurring defensive compounds The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Ibarra, Yessenia Michelle. 2013. Characterization of human TRPA1 and TRPV1 channels in response to naturally occurring defensive compounds. Doctoral dissertation, Harvard University. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:11156673 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA © 2013 – Yessenia Michelle Ibarra All rights reserved. Dissertation Advisor: David E. Clapham Yessenia Michelle Ibarra Characterization of human TRPA1 and TRPV1 channels in response to naturally occurring defensive compounds Abstract The transient receptor potential channels, ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), are non-selective cation-permeable channels that have retained their function as chemical sensors since their first appearance in metazoan species several hundred million years ago. In vertebrates, TRP channels have evolved multiple functions which make it difficult to understand exactly how they transmit signals to the brain that are interpreted very differently. For example, TRPA1 and TRPV1 are sensitive to various chemicals and activation of these channels produce sensations with opposing effects. Pain is felt when TRPV1 is activated by spider toxins, but activation by plant cannabidiol results in a pain-relieving sensation. Similarly, TRPA1 activation by delta- tetrahydrocannabinol is reported to relieve symptoms of pain, but TRPA1 activation by the active ingredient in wasabi results in a repulsive or noxious sensation.