# US 9,750,707 B2 · Methods and compositions for administration of TRPV1 agonists > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 9,750,707 B2 - Document ID: US9750707B2 - Status: Granted - Kind: B2 - Application number: 14/255,630 - Filed: 2014-04-17 - Published: 2015-03-12 - Granted: 2017-09-05 - Earliest claimed: 2003-04-10 - Assignees: Acorda Therapeutics, Inc. - Applicants: Acorda Therapeutics, Inc. - Inventors: Naweed Muhammad; Gene Curtis Jamieson; Keith R. Bley; Sanjay Chanda - Web page: https://patentgrep.com/patent/US9750707B2 ## CPC - A61K 31/165: having aromatic rings, e.g. colchicine, atenolol, progabide - A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)} - A61K 9/08: Solutions {(composition of solutions A61K47/00)} - A61K 9/1075: {Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence)} - A61K 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61K 47/08: containing oxygen, {e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides} - A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers - A61K 47/12: Carboxylic acids; Salts or anhydrides thereof - A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system - A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis - A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants - A61P 3/10: for hyperglycaemia, e.g. antidiabetics - A61P 11/02: Nasal agents, e.g. decongestants - A61P 13/08: of the prostate - A61P 13/10: of the bladder - A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives - A61P 15/02: for disorders of the vagina - A61P 17/00: Drugs for dermatological disorders - A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like - A61P 17/04: Antipruritics - A61P 17/06: Antipsoriatics - A61P 17/12: Keratolytics, e.g. wart or anti-corn preparations - A61P 17/16: Emollients or protectives, e.g. against radiation - A61P 23/02: Local anaesthetics - A61P 25/00: Drugs for disorders of the nervous system - A61P 25/02: for peripheral neuropathies - A61P 25/04: Centrally acting analgesics, e.g. opioids - A61P 25/06: Antimigraine agents - A61P 27/16: Otologicals - A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] - A61P 29/02: without antiinflammatory effect - A61P 31/10: Antimycotics - A61P 31/18: for HIV - A61P 31/22: for herpes viruses - A61P 35/00: Antineoplastic agents - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Compositions are provided that contain a TRPV1 agonist, such as capsaicin, and a solvent system. Topical application of the composition results in rapid delivery of agonist to the dermis and epidermis. Method of using the compositions for reducing nociceptive nerve fiber function in subjects, and for treatment of capsaicin-responsive conditions are also provided. ## Claims ### Claim 1 A method of delivering a TRPV1 agonist to the epidermis and dermis underlying a 1 cm2 area of a skin or mucosal surface of a mammal, comprising non-occlusively or non-adherently contacting the area with a composition comprising the TRPV1 agonist and at least one penetration enhancer, wherein 30 minutes after said contacting at least about 3 nmoles of the TRPV1 agonist is retained in the epidermis and dermis. ### Claim 2 (depends on 1) The method of claim 1 wherein 15 minutes after said contacting at least about 3 nmoles of the TRPV1 agonist is retained in the epidermis and dermis. ### Claim 3 (depends on 2) The method of claim 2 wherein at least about 32 nmoles of the TRPV1 agonist is retained in the epidermis and dermis. ### Claim 4 (depends on 3) The method of claim 3 wherein at least about 49 nmoles of the TRPV1 agonist is retained in the epidermis and dermis. ### Claim 5 (depends on 4) The method of claim 4 wherein at least about 65 nmoles of the TRPV1 agonist is retained in the epidermis and dermis. ### Claim 6 (depends on 2) The method of claim 2 wherein at least about 16 nmoles of the TRPV1 agonist is retained in the epidermis and dermis. ### Claim 7 (depends on 2) The method of claim 2 wherein the TRPV1 agonist is capsaicin. ### Claim 8 (depends on 2) The method of claim 2 wherein the area contacted is skin. ### Claim 9 (depends on 8) The method of claim 8 wherein the mammal is a human. ### Claim 10 (depends on 9) The method of claim 9 wherein the human suffers from a capsaicin responsive condition. ### Claim 11 (depends on 2) The method of claim 2 wherein the density of functional nociceptive nerve fibers in the epidermis and dermis is decreased by at least about 20% when measured from 2 to 7 days after said contacting step. ### Claim 12 (depends on 2) The method of claim 2 wherein the composition delivers at least about 3 nmoles of the TRPV1 agonist to skin as measured in a mouse skin absorption assay. ### Claim 13 (depends on 2) The method of claim 2 wherein the at least one penetration enhancer is selected from the group consisting of ethers, esters, alcohols, fatty acids, fatty acid esters, fatty alcohols, polyols, terpenes, and amines. ### Claim 14 A method of reducing the density of functional nociceptive nerve fibers in a selected region of a subject, comprising non-occlusively or non-adherently contacting the selected region with an immediate-release composition that comprises a TRPV1 agonist and one or more penetration enhancers, wherein said composition delivers at least about 3 nmoles of the TRPV1 agonist to skin as measured in a mouse skin absorption assay. ### Claim 15 A method of reducing the density of functional nociceptive nerve fibers in a selected region of a subject, comprising non-occlusively or non-adherently contacting the selected region with a composition that comprises a TRPV1 agonist and a solvent system comprising one or more penetration enhancers, wherein said composition delivers at least about 3 nmoles of the TRPV1 agonist to skin as measured in a mouse skin absorption assay, and wherein at least about 5 μl of the composition is delivered to each cm2 of the selected region in about 15 minutes. ### Claim 16 (depends on 14) The method of claim 14 wherein the selected region is on the surface of skin or mucosa. ### Claim 17 (depends on 14) The method of claim 14 wherein said composition delivers at least about 6 nmoles of the TRPV1 agonist to skin. ### Claim 18 (depends on 17) The method of claim 17 wherein said composition delivers at least about 16 nmoles of the TRPV1 agonist to skin. ### Claim 19 (depends on 18) The method of claim 18 wherein said composition delivers at least about 32 nmoles of the TRPV1 agonist to skin. ### Claim 20 (depends on 19) The method of claim 19 wherein said composition delivers at least about 49 nmoles of the TRPV1 agonist to skin. ### Claim 21 (depends on 20) The method of claim 20 wherein said composition delivers at least about 65 nmoles of the TRPV1 agonist to skin. ### Claim 22 (depends on 14) The method of claim 14 wherein said composition delivers from about 5 nmoles to about 290 moles of the TRPV1 agonist to skin. ### Claim 23 (depends on 14) The method of claim 14 wherein the depot effect of said contacting is less than about 0.25 as measured in a mouse skin absorption assay. ### Claim 24 (depends on 23) The method of claim 23 wherein the depot effect is less than about 0.1. ### Claim 25 (depends on 24) The method of claim 24 wherein the depot effect is less than about 0.02. ### Claim 26 (depends on 25) The method of claim 25 wherein the depot effect is less than about 0.001. ### Claim 27 (depends on 14) The method of claim 14 wherein the depot effect is in a range of about 0.001 to about 0.25. ### Claim 28 (depends on 14) The method of claim 14 wherein the distribution effect of said contacting is in the range of 0.5 to 2, as measured in a mouse skin absorption assay. ### Claim 29 (depends on 14) The method of claim 14 wherein the composition comprises the TRPV1 agonist and a solvent system, wherein penetration enhancer(s) make up at least 20% (v/v) of the solvent system. ### Claim 30 (depends on 29) The method of claim 29 wherein penetration enhancer(s) make up at least 50% (v/v) of the solvent system. ### Claim 31 (depends on 30) The method of claim 30 wherein penetration enhancer(s) make up at least 90% (v/v) of the solvent system. ### Claim 32 (depends on 31) The method of claim 31 wherein penetration enhancer(s) make up at least 95% (v/v) of the solvent system. ### Claim 33 (depends on 14) The method of claim 14 wherein the one or more penetration enhancers is selected from the group consisting of ethers, esters, alcohols, fatty acids, fatty acid esters, fatty alcohols, polyols, terpenes, and amines. ### Claim 34 (depends on 14) The method of claim 14 wherein the one or more penetration enhancers is selected from the group consisting of fatty alcohols and terpenes. ### Claim 35 (depends on 14) The method of claim 14 wherein the one or more penetration enhancers is selected from the group consisting of 1-menthone, dimethyl isosorbide, caprylic alcohol, lauryl alcohol, oleyl alcohol, ethylene glycol, diethylene glycol, triethylene glycol, butylene glycol, valeric acid, pelargonic acid, caproic acid, caprylic acid, lauric acid, oleic acid, isovaleric acid, isopropyl butyrate, isopropyl hexanoate, butyl acetate, methyl acetate, methyl valerate, ethyl oleate, poloxamer, d-piperitone, methylnonenoic acid, methylnonenoic alcohol, and d-pulegone. ### Claim 36 (depends on 14) The method of claim 14 wherein said composition comprises said TRPV1 agonist at a concentration of from 0.05% (w/v) to 60% (w/v). ### Claim 37 (depends on 36) The method of claim 36 wherein the TRPV1 agonist is a vanilloid. ### Claim 38 (depends on 37) The method of claim 37 wherein the TRPV1 agonist is capsaicin. ### Claim 39 (depends on 36) The method of claim 36 wherein said composition comprises said TRPV1 agonist at a concentration of from 1% (w/v) to 20% (w/v). ### Claim 40 (depends on 14) The method of claim 14 wherein the subject is a human. ### Claim 41 (depends on 14) The method of claim 14 wherein said contacting is by topical application or instillation. ### Claim 42 (depends on 14) The method of claim 14 wherein a 15 minute application of the composition to skin of a mammal results in a decrease in the density of functional nociceptive nerve fibers by at least about 50%, wherein the mammal is selected from the group consisting of a mouse and a human. ### Claim 43 (depends on 40) The method of claim 40 wherein the subject suffers from a capsaicin-responsive condition. ### Claim 44 (depends on 43) The method of claim 43 wherein the capsaicin-responsive condition is neuropathic 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. ### Claim 45 A method of treating a capsaicin-responsive condition in a subject, comprising non-occlusive or non-adherent administration of a composition that comprises a TRPV1 agonist and at least one penetration enhancer, wherein said composition delivers at least about 3 nmoles of the TRPV1 agonist to skin as measured in a mouse skin absorption assay. ### Claim 46 (depends on 45) The method of claim 45 wherein the composition comprises at least two penetration enhancers. ### Claim 47 (depends on 45) The method of claim 45 wherein the composition is applied to an area on the surface of skin, mucosa, or endothelium. ### Claim 48 (depends on 45) The method of claim 45 wherein said composition delivers at least about 6 nmoles of the TRPV1 agonist to skin. ### Claim 49 (depends on 48) The method of claim 48 wherein said composition delivers at least about 16 nmoles of the TRPV1 agonist to skin. ### Claim 50 (depends on 49) The method of claim 49 wherein said composition delivers at least about 32 nmoles of the TRPV1 agonist to skin. ### Claim 51 (depends on 50) The method of claim 50 wherein said composition delivers at least about 49 nmoles of the TRPV1 agonist to skin. ### Claim 52 (depends on 51) The method of claim 51 wherein said composition delivers at least about 65 nmoles of the TRPV1 agonist to skin. ### Claim 53 (depends on 45) The method of claim 45 wherein said composition delivers from about 5 nmoles to about 290 nmoles of the TRPV1 agonist to skin. ### Claim 54 (depends on 45) The method of claim 45 wherein the depot effect of said contacting is less than about 0.25 as measured in a mouse skin absorption assay. ### Claim 55 (depends on 54) The method of claim 54 wherein the depot effect is less than about 0.1. ### Claim 56 (depends on 55) The method of claim 55 wherein the depot effect is less than about 0.02. ### Claim 57 (depends on 56) The method of claim 56 wherein the depot effect is less than about 0.001. ### Claim 58 (depends on 54) The method of claim 54 wherein the depot effect is in a range of about 0.001 to about 0.25. ### Claim 59 (depends on 45) The method of claim 45 wherein the distribution effect of said administration is in the range of 0.5 to 2 as measured in a mouse skin absorption assay. ### Claim 60 (depends on 45) The method of claim 45 wherein the composition comprises the TRPV1 agonist and a solvent system, and wherein the at least one penetration enhancer makes up at least 20% (v/v) of the solvent system. ### Claim 61 (depends on 60) The method of claim 60 wherein the at least one penetration enhancer makes up at least 50% (v/v) of the solvent system. ### Claim 62 (depends on 61) The method of claim 61 wherein the at least one penetration enhancer makes up at least 90% (v/v) of the solvent system. ### Claim 63 (depends on 62) The method of claim 62 wherein the at least one penetration enhancer makes up at least 95% (v/v) of the solvent system. ### Claim 64 (depends on 60) The method of claim 60 wherein the solvent system comprises a penetration enhancer selected from the group consisting of ethers, esters, alcohols, fatty acids, fatty acid esters, fatty alcohols, polyols, terpenes, and amines. ### Claim 65 (depends on 64) The method of claim 64 wherein the solvent system comprises a penetration enhancer selected from the group consisting of fatty alcohols and terpenes. ### Claim 66 (depends on 65) The method of claim 65 wherein said solvent system comprises a penetration enhancer selected from the group consisting of 1-menthone, dimethyl isosorbide, caprylic alcohol, lauryl alcohol, oleyl alcohol, ethylene glycol, diethylene glycol, triethylene glycol, butylene glycol, valeric acid, pelargonic acid, caproic acid, caprylic acid, lauric acid, oleic acid, isovaleric acid, isopropyl butyrate, isopropyl hexanoate, butyl acetate, methyl acetate, methyl valerate, ethyl oleate, poloxamer, d-piperitone, methylnonenoic acid, methylnonenoic alcohol, and d-pulegone. ### Claim 67 (depends on 45) The method of claim 45 wherein said composition comprises said TRPV1 agonist at a concentration of from 0.05% (w/v) to 60% (w/v). ### Claim 68 (depends on 67) The method of claim 67 wherein the TRPV1 agonist is a vanilloid. ### Claim 69 (depends on 68) The method of claim 68 wherein the TRPV1 agonist is capsaicin. ### Claim 70 (depends on 69) The method of claim 69 wherein said composition comprises said TRPV1 agonist at a concentration of from 1% (w/v) to 20% (w/v). ### Claim 71 (depends on 70) The method of claim 70 wherein a 15 minute application of the composition to skin of a mammal results in a decrease in the density of functional nociceptive nerve fibers by at least about 20% when measured 2 to 7 days after said administration step. ### Claim 72 (depends on 71) The method of claim 71 wherein a 15 minute application of the composition to skin of a mammal results in a decrease in the density of functional nociceptive nerve fibers by at least about 50% when measured 7 days after said administration step. ### Claim 73 (depends on 14) The method of claim 14 wherein the density of functional nociceptive nerve fibers in the epidermis and dermis underlying said region is decreased by at least about 20% when measured 7 days after said administration step. ### Claim 74 (depends on 45) The method of claim 45 wherein the composition is administered topically. ### Claim 75 (depends on 74) The method of claim 74 wherein the composition is administered by instillation. ### Claim 76 (depends on 45) The method of claim 45 wherein the composition is administered by injection. ### Claim 77 (depends on 45) The method of claim 45 wherein the composition is administered in the form of a microemulsion. ### Claim 78 (depends on 45) The method of claim 45 wherein the capsaicin-responsive condition is neuropathic 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. ### Claim 79 (depends on 78) The method of claim 78 wherein the neuropathic pain is associated with diabetic neuropathy, postherpetic neuralgia, HIV/AIDS, traumatic injury, complex regional pain syndrome, trigeminal neuralgia, erythromelalgia or phantom pain. ### Claim 80 (depends on 79) The method claim 79 wherein one or two applications of the composition provide persistent relief. ### Claim 81 (depends on 80) The method claim 80 wherein one application of the composition provides persistent relief. ### Claim 82 (depends on 45) The method of claim 45 wherein the composition is administered to an area on the surface of the skin and subsequent to administration the area is cleaned to remove any residual TRPV1 agonist. ### Claim 83 (depends on 82) The method of claim 82 wherein the area is cleaned using a composition containing at least 60% (w/w) polyethylene glycol. ### Claim 84 (depends on 45) The method of claim 45 wherein the composition further comprises one or more additional therapeutically active agents.