CA2283929C - Method for treating headache pain with topical local anesthetic compositions - Google Patents
Method for treating headache pain with topical local anesthetic compositions Download PDFInfo
- Publication number
- CA2283929C CA2283929C CA002283929A CA2283929A CA2283929C CA 2283929 C CA2283929 C CA 2283929C CA 002283929 A CA002283929 A CA 002283929A CA 2283929 A CA2283929 A CA 2283929A CA 2283929 C CA2283929 C CA 2283929C
- Authority
- CA
- Canada
- Prior art keywords
- local anesthetic
- composition
- topical
- headache pain
- eucalyptol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000003589 local anesthetic agent Substances 0.000 title claims abstract description 81
- 239000000203 mixture Substances 0.000 title claims abstract description 76
- 208000002193 Pain Diseases 0.000 title claims abstract description 55
- 230000036407 pain Effects 0.000 title claims abstract description 55
- 230000000699 topical effect Effects 0.000 title claims abstract description 48
- 206010019233 Headaches Diseases 0.000 title claims abstract description 41
- 231100000869 headache Toxicity 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 title abstract description 22
- 210000005036 nerve Anatomy 0.000 claims abstract description 44
- WEEGYLXZBRQIMU-UHFFFAOYSA-N 1,8-cineole Natural products C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 claims abstract description 30
- WEEGYLXZBRQIMU-WAAGHKOSSA-N Eucalyptol Chemical compound C1C[C@H]2CC[C@]1(C)OC2(C)C WEEGYLXZBRQIMU-WAAGHKOSSA-N 0.000 claims abstract description 28
- 229960005233 cineole Drugs 0.000 claims abstract description 28
- 239000003961 penetration enhancing agent Substances 0.000 claims abstract description 23
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 claims description 12
- MMOXZBCLCQITDF-UHFFFAOYSA-N N,N-diethyl-m-toluamide Chemical group CCN(CC)C(=O)C1=CC=CC(C)=C1 MMOXZBCLCQITDF-UHFFFAOYSA-N 0.000 claims description 7
- 229960005274 benzocaine Drugs 0.000 claims description 7
- 230000000903 blocking effect Effects 0.000 claims description 6
- 239000000853 adhesive Substances 0.000 claims description 5
- 230000001070 adhesive effect Effects 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 239000011505 plaster Substances 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 2
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 claims 1
- 229960003150 bupivacaine Drugs 0.000 claims 1
- 230000035515 penetration Effects 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 229960005015 local anesthetics Drugs 0.000 description 9
- 239000000499 gel Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000003349 gelling agent Substances 0.000 description 4
- 208000006561 Cluster Headache Diseases 0.000 description 3
- 208000019695 Migraine disease Diseases 0.000 description 3
- 208000018912 cluster headache syndrome Diseases 0.000 description 3
- 239000006184 cosolvent Substances 0.000 description 3
- 229960004194 lidocaine Drugs 0.000 description 3
- 206010027599 migraine Diseases 0.000 description 3
- 239000002736 nonionic surfactant Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000012049 topical pharmaceutical composition Substances 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- 206010034960 Photophobia Diseases 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000005684 electric field Effects 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000003193 general anesthetic agent Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 208000013469 light sensitivity Diseases 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- MVFGUOIZUNYYSO-UHFFFAOYSA-N prilocaine Chemical compound CCCNC(C)C(=O)NC1=CC=CC=C1C MVFGUOIZUNYYSO-UHFFFAOYSA-N 0.000 description 2
- 229960001807 prilocaine Drugs 0.000 description 2
- NBFQYHKHPBMJJV-UHFFFAOYSA-N risocaine Chemical compound CCCOC(=O)C1=CC=C(N)C=C1 NBFQYHKHPBMJJV-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- GHSCYMOJHVOGDJ-UHFFFAOYSA-N 2-(diethylamino)ethyl 4-amino-2-hydroxybenzoate Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1O GHSCYMOJHVOGDJ-UHFFFAOYSA-N 0.000 description 1
- KRQUFUKTQHISJB-YYADALCUSA-N 2-[(E)-N-[2-(4-chlorophenoxy)propoxy]-C-propylcarbonimidoyl]-3-hydroxy-5-(thian-3-yl)cyclohex-2-en-1-one Chemical compound CCC\C(=N/OCC(C)OC1=CC=C(Cl)C=C1)C1=C(O)CC(CC1=O)C1CCCSC1 KRQUFUKTQHISJB-YYADALCUSA-N 0.000 description 1
- PUYOAVGNCWPANW-UHFFFAOYSA-N 2-methylpropyl 4-aminobenzoate Chemical compound CC(C)COC(=O)C1=CC=C(N)C=C1 PUYOAVGNCWPANW-UHFFFAOYSA-N 0.000 description 1
- 206010009094 Chronic paroxysmal hemicrania Diseases 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 229940019097 EMLA Drugs 0.000 description 1
- 244000166124 Eucalyptus globulus Species 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010027603 Migraine headaches Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920001328 Polyvinylidene chloride Polymers 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 208000008548 Tension-Type Headache Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 239000004015 abortifacient agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- IUWVALYLNVXWKX-UHFFFAOYSA-N butamben Chemical compound CCCCOC(=O)C1=CC=C(N)C=C1 IUWVALYLNVXWKX-UHFFFAOYSA-N 0.000 description 1
- 229960000400 butamben Drugs 0.000 description 1
- VWYQKFLLGRBICZ-UHFFFAOYSA-N butanilicaine Chemical compound CCCCNCC(=O)NC1=C(C)C=CC=C1Cl VWYQKFLLGRBICZ-UHFFFAOYSA-N 0.000 description 1
- 229960001290 butanilicaine Drugs 0.000 description 1
- 229940049638 carbomer homopolymer type c Drugs 0.000 description 1
- 229940043234 carbomer-940 Drugs 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- RFFOTVCVTJUTAD-UHFFFAOYSA-N cineole Natural products C1CC2(C)CCC1(C(C)C)O2 RFFOTVCVTJUTAD-UHFFFAOYSA-N 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229960001673 diethyltoluamide Drugs 0.000 description 1
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 description 1
- 229940043276 diisopropanolamine Drugs 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000374 eutectic mixture Substances 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- CVHGCWVMTZWGAY-UHFFFAOYSA-N fomocaine Chemical compound C=1C=C(COC=2C=CC=CC=2)C=CC=1CCCN1CCOCC1 CVHGCWVMTZWGAY-UHFFFAOYSA-N 0.000 description 1
- 229950003051 fomocaine Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229950000998 hydroxyprocaine Drugs 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000000077 insect repellent Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- UYXHCVFXDBNRQW-UHFFFAOYSA-N naepaine Chemical compound CCCCCNCCOC(=O)C1=CC=C(N)C=C1 UYXHCVFXDBNRQW-UHFFFAOYSA-N 0.000 description 1
- 229950009121 naepaine Drugs 0.000 description 1
- 229940090008 naprosyn Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 230000007830 nerve conduction Effects 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- HKOURKRGAFKVFP-UHFFFAOYSA-N octacaine Chemical compound CCN(CC)C(C)CC(=O)NC1=CC=CC=C1 HKOURKRGAFKVFP-UHFFFAOYSA-N 0.000 description 1
- 229950009333 octacaine Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- OWWVHQUOYSPNNE-UHFFFAOYSA-N parethoxycaine Chemical compound CCOC1=CC=C(C(=O)OCCN(CC)CC)C=C1 OWWVHQUOYSPNNE-UHFFFAOYSA-N 0.000 description 1
- 229960003899 parethoxycaine Drugs 0.000 description 1
- 208000007777 paroxysmal Hemicrania Diseases 0.000 description 1
- 230000037368 penetrate the skin Effects 0.000 description 1
- BMIJYAZXNZEMLI-UHFFFAOYSA-N piridocaine Chemical compound NC1=CC=CC=C1C(=O)OCCC1NCCCC1 BMIJYAZXNZEMLI-UHFFFAOYSA-N 0.000 description 1
- 229950001038 piridocaine Drugs 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- -1 polyethylene Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 239000005033 polyvinylidene chloride Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000002694 regional anesthesia Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229950003447 risocaine Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229920003051 synthetic elastomer Polymers 0.000 description 1
- 239000005061 synthetic rubber Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- UDKICLZCJWQTLS-UHFFFAOYSA-N tolycaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C(=O)OC UDKICLZCJWQTLS-UHFFFAOYSA-N 0.000 description 1
- 229950006609 tolycaine Drugs 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- GOZBHBFUQHMKQB-UHFFFAOYSA-N trimecaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=C(C)C=C1C GOZBHBFUQHMKQB-UHFFFAOYSA-N 0.000 description 1
- 229950002569 trimecaine Drugs 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
Classifications
-
- 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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
- A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Emergency Medicine (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Methods are provided for the treatment of a host suffering from headache pain with topical applications of a local anesthetic. The topical local anesthetic composition comprises an effective amount of a local anesthetic in combination with eucalyptol as a penetration enhancing agent, and optionally an additional penetration enhancing agent. The topical local anesthetic composition is applied to a keratinized skin site proximal to target nerves associated with the headache pain, usually to the supraorbital or occipital regions of the head. Upon application of the topical composition, the local anesthetic rapidly penetrates the skin to block conduction in the target nerves and provide pain relief to the host.
Description
METHOD FOR TREATING HEADACHE PAIN WITH TOPICAL
LOCAL ANESTHETIC COMPOSITIONS
INTRODUCTION
Field of the Invention The field of this invention is the treatment of headache pain.
Backcrround Headaches are a common problem affecting a large segment of the population. Headaches, such as tension type and migraine headaches, occur both intermittently and chronically, and can arise in response to variety of stimulants, including stress, injury, toxins in the environment and the like.
A variety of therapeutic agents have been developed for use in the treatment of patients suffering from headache pain. Some agents, such as aspirin, acetaminophen, vasoconstrictors and NSAIDs, e.g.
ibuprofen and naprosyn, are administered systemically.
Despite the prevalence of this form of treatment for headache pain, in some cases, systemic administration is not recommended. For example, oral administration of aspirin can result in stomach upset and patient discomfort. Furthermore, the agent can exert host systemic toxicity which may outweigh any therapeutic benefits provided by the agent. Finally, since the agent is administered systemically, its~effects are also systemic, which may not be desired.
In view of the above problems and disadvantages associated with therapeutic agents that are administered systemically, regional administration of local anesthetics which selectively block conduction in target nerves is a desirable alternative for the treatment of headache pain. Use of local anesthetics is desirable because nerve conduction can be selectively blocked in only those nerves associated with the headache pain.
Although use of local anesthetics in the treatment of headache pain is desirable, administration of an effective amount of the local anesthetic to the target nerves is difficult and/or inconvenient.
Z5 For example, a local anesthetic can be injected directly at the site of nerves associated with headache pain, e.g. the occipital and supraorbital nerves to effect a nerve block and thereby provide pain relief. See Garron, "Relieving Pain with Nerve Blocks," Geriatrics (1978) 33: 49-57. Although this method is effective in providing headache pain relief, because the local anesthetic is injected it must be administered by trained personnel. Furthermore, the patient must bear the discomfort associated with the injection of the local anesthetic.
Because of these disadvantages of administration by injection, the topical administration of local anesthetics is a desirable alternative mode of administration. However, local anesthetics by themselves .
r ~ . _, do not readily penetrate the keratinized layer of the skin. See Review of Medical Pharmacology (Meyers et al.
ed., 1978) pp. 217-226. Thus, intranasal application of local anesthetics has found use in the treatment of headache pain. See Brandt et al., "Cluster headache and chronic paroxysmal hemicrania: current therapy,"
Nervenarzt (1991) 62: 329-339.
For topical administration of local anesthetics to keratinized skin surfaces, additional measures must be taken to provide for penetration of the local anesthetic across the keratinized skin surface. One means of providing for penetration of the local anesthetic across the skin surface is to employ iontophoretic techniques, where an electric field is applied to the topical local anesthetic composition. The local anesthetic penetrates the keratinized skin surface under the influence of the applied electric field.
Another means of providing for penetration of keratinized skin is to employ formulations which promote local anesthetic penetration. Although such formulations are available and have been employed for a variety of applications, currently available topical local anesthetic formulations have not found widespread use for the treatment of headache pain. One reason that currently available formulations have not found widespread use for the treatment of headache pain is that an effective amount of the anesthetic agent does not penetrate the skin rapidly enough to provide pain relief in a sufficiently short period of time. For example, when EMLA
LOCAL ANESTHETIC COMPOSITIONS
INTRODUCTION
Field of the Invention The field of this invention is the treatment of headache pain.
Backcrround Headaches are a common problem affecting a large segment of the population. Headaches, such as tension type and migraine headaches, occur both intermittently and chronically, and can arise in response to variety of stimulants, including stress, injury, toxins in the environment and the like.
A variety of therapeutic agents have been developed for use in the treatment of patients suffering from headache pain. Some agents, such as aspirin, acetaminophen, vasoconstrictors and NSAIDs, e.g.
ibuprofen and naprosyn, are administered systemically.
Despite the prevalence of this form of treatment for headache pain, in some cases, systemic administration is not recommended. For example, oral administration of aspirin can result in stomach upset and patient discomfort. Furthermore, the agent can exert host systemic toxicity which may outweigh any therapeutic benefits provided by the agent. Finally, since the agent is administered systemically, its~effects are also systemic, which may not be desired.
In view of the above problems and disadvantages associated with therapeutic agents that are administered systemically, regional administration of local anesthetics which selectively block conduction in target nerves is a desirable alternative for the treatment of headache pain. Use of local anesthetics is desirable because nerve conduction can be selectively blocked in only those nerves associated with the headache pain.
Although use of local anesthetics in the treatment of headache pain is desirable, administration of an effective amount of the local anesthetic to the target nerves is difficult and/or inconvenient.
Z5 For example, a local anesthetic can be injected directly at the site of nerves associated with headache pain, e.g. the occipital and supraorbital nerves to effect a nerve block and thereby provide pain relief. See Garron, "Relieving Pain with Nerve Blocks," Geriatrics (1978) 33: 49-57. Although this method is effective in providing headache pain relief, because the local anesthetic is injected it must be administered by trained personnel. Furthermore, the patient must bear the discomfort associated with the injection of the local anesthetic.
Because of these disadvantages of administration by injection, the topical administration of local anesthetics is a desirable alternative mode of administration. However, local anesthetics by themselves .
r ~ . _, do not readily penetrate the keratinized layer of the skin. See Review of Medical Pharmacology (Meyers et al.
ed., 1978) pp. 217-226. Thus, intranasal application of local anesthetics has found use in the treatment of headache pain. See Brandt et al., "Cluster headache and chronic paroxysmal hemicrania: current therapy,"
Nervenarzt (1991) 62: 329-339.
For topical administration of local anesthetics to keratinized skin surfaces, additional measures must be taken to provide for penetration of the local anesthetic across the keratinized skin surface. One means of providing for penetration of the local anesthetic across the skin surface is to employ iontophoretic techniques, where an electric field is applied to the topical local anesthetic composition. The local anesthetic penetrates the keratinized skin surface under the influence of the applied electric field.
Another means of providing for penetration of keratinized skin is to employ formulations which promote local anesthetic penetration. Although such formulations are available and have been employed for a variety of applications, currently available topical local anesthetic formulations have not found widespread use for the treatment of headache pain. One reason that currently available formulations have not found widespread use for the treatment of headache pain is that an effective amount of the anesthetic agent does not penetrate the skin rapidly enough to provide pain relief in a sufficiently short period of time. For example, when EMLA
(a eutectic mixture crf lidocaine~and prilocaine) is topically applied to a keratinized skin surface, it must be applied under an occlusive dressing for at least one hour before analgesia is experienced by the host. See Physician's Desk Reference, 1994, pp 544.
Thus, there is continued interest in the identification of topical local anesthetic formulations which are suitable for use in the treatment of headache pain. Such topical formulations should provide for rapid penetration of an effective amount of the local anesthetic through the skin surface, and thereby provide for rapid pain relief.
Relevant Literature U.S. Patent No. 4,440,777 describes topical applications comprising eucalyptol as an enhancing agent.
Other patents of interest include U.S. Pat. Nos.:
4,588,580; 4,911,707; 5,069,909; 5,070,084; 5,330,452;
and 5,368,860.
Kittrelle et al., "Cluster Headache. Local Anesthetic Abortive Agents, " Arch. Neurol. (1985) 42 496-498 reports the application of a 4% lidocaine solution to the sphenopalantine fossa in order to treat nitrate induced cluster headache pain.
SUMMARY OF THE INVENTION
Methods are provided for the treatment of a host suffering from headache pain with topical local anesthetic compositions. Topical local anesthetic _ .~.. . r .
Thus, there is continued interest in the identification of topical local anesthetic formulations which are suitable for use in the treatment of headache pain. Such topical formulations should provide for rapid penetration of an effective amount of the local anesthetic through the skin surface, and thereby provide for rapid pain relief.
Relevant Literature U.S. Patent No. 4,440,777 describes topical applications comprising eucalyptol as an enhancing agent.
Other patents of interest include U.S. Pat. Nos.:
4,588,580; 4,911,707; 5,069,909; 5,070,084; 5,330,452;
and 5,368,860.
Kittrelle et al., "Cluster Headache. Local Anesthetic Abortive Agents, " Arch. Neurol. (1985) 42 496-498 reports the application of a 4% lidocaine solution to the sphenopalantine fossa in order to treat nitrate induced cluster headache pain.
SUMMARY OF THE INVENTION
Methods are provided for the treatment of a host suffering from headache pain with topical local anesthetic compositions. Topical local anesthetic _ .~.. . r .
compositions employed in the subject methods comprise an effective amount of a local anesthetic in combination with eucalyptol as a penetration enhancing agent. The local anesthetic compositions are applied to a keratinized skin site proximal to target nerves associated with the headache pain.
Upon application, the local anesthetic rapidly penetrates the skin surface to reach, and block conduction in, the target nerves and provide for rapid pain relief.
In various embodiments there is provided the use of a composition comprising a local anesthetic in combination with eucalyptol as a penetration enhancing agent for blocking conduction in target nerves selected from the group consisting of occipital and supraorbital nerves in the topical treatment of headache pain in a host, wherein the composition is for topical application at a keratinized skin site proximal to the target nerves.
In various embodiments there is provided the use of a local anesthetic, wherein the local anesthetic is an amine linked through a connecting group to an aromatic group, in combination with eucalyptol as a penetration enhancing agent, and with an additional penetration enhancing agent, for blocking the conduction in target nerves selected from the group consisting of occipital and supraorbital nerves in the topical treatment of headache pain in a host suffering from headache pain, wherein the local anesthetic is for topical application at a keratinized skin site proximal to the target nerves.
In various embodiments there is provided the use of a composition comprising (a) an effective amount of benzocaine, (b) eucalyptol and (c) N,N-diethyl-m-toluamide for blocking conduction in target nerves selected from the group consisting of occipital and supraorbital nerves in the topical treatment of headache pain in a host suffering from headache pain, - 5a -wherein the composition is for topical application at a keratinized skin site proximal to said target nerves.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
Methods are provided for the treatment of a host suffering from headache pain through application of topical local anesthetic compositions. The local anesthetic compositions employed in the subject methods comprise an effective amount of a local anesthetic in combination with eucalyptol as a penetration enhancing agent and provide for rapid penetration of the local anesthetic agent through a keratinized skin surface. In the subject methods, the local anesthetic composition is topically applied to a skin site proximal to target nerves associated with the headache pain. Upon application, the local anesthetic agent penetrates the skin to block conduction in the target nerves and provide pain relief to the host.
Topical compositions employed in the subject method will include a local anesthetic as the active agent. Although two or more local anesthetic agents may be present in the subject compositions, generally the subject compositions will comprise a single local anesthetic agent. The local anesthetic employed in the subject methods will be an anesthetic which, when administered in the topical formulations, rapidly penetrates a keratinized skin surface to block conduction in nerves underlying the skin surface. The local anesthetic will have a molecular weight and melting point that is compatible with transport across the keratinized skin surface. Generally, the molecular weight of the l0 local anesthetic will not exceed about 300 dal, and will more usually not exceed about 250 dal. The melting point of the local anesthetic will be less than about 100 °C.
Generally, the local anesthetic will be a compound comprised of a secondary or tertiary amine linked through a connecting group to an aromatic group. The local anesthetic will be an alkanyl compound of from about 9 to carbon atoms. Because the composition is applied topically, the local anesthetic will generally be present in the composition as a free base to promote penetration 20 of the agent through the skin surface. A large number of local anesthetics are known in the art, many of which are suitable for topical application. Suitable local anesthetics include lidocaine, butamben, butanilicaine, ethyl aminobenzoate, fomocaine, hydroxyprocaine, isobutyl p-aminobenzoate, naepaine, octacaine, parethoxycaine, piridocaine, prilocaine, procaine, risocaine, tolycaine, trimecaine, particularly ethylaminobenzoate (benzocaine).
The amount of local anesthetic present in the subject compositions will be sufficient to provide an effective amount of the agent when topically administered according to the subject methods. The precise amount of anesthetic agent present in the topical formulation will depend on the particular agent employed, but will generally range from 5 to 50 % by weight, usually from about 10 to 40 by weight.
Critical to the topical applications employed in the subject methods is eucalyptol, which serves as a penetration enhancing agent for the local anesthetic.
Eucalyptol (1,3,3-trimethyl-2-oxabicyclo[2,2,2]-octane) is the chief constituent of oil of eucalyptus and is also known as cineole and cajeputol. Eucalyptol is known in the art, having found use as an insect repellant and as a flavoring agent. The amount of eucalyptol present in the composition will range from about 10 to 80%, usually from about 10 to 50 % by weight, and more usually from about to 40 % by weight of the composition.
Optionally, the subject composition may further comprise one or more additional penetration enhancing 20 agents which work in combination with the eucalyptol to provide for rapid penetration of the local anesthetic.
Additional penetration enhancing agents will be capable of rapid penetration of the skin and be pharmaceutically acceptable, i.e. non-toxic to the host at the levels at which they are present in the composition. Examples of additional penetration enhancing agents which may find use in the subject compositions include: propylene glycol and N-methyl-2-pyrrolidone. An additional penetration enhancing agent that finds particular use in combination _.
_ g _ with eucalyptol in the subject compositions is N,N-diethyl-m-toluamide (DEET). When present, the amount of this additional penetration enhancing agent in the subject compositions will vary depending on the particular agent, as well as the Iocal anesthetic present in the composition. The amount of additional penetration enhancing agent or agents in the subject compositions will range from 10 to 80 o by weight, usually from about 30 to 60 % by weight. Generally, the ratio of eucalyptol to additional penetration enhancing agent in the subject compositions will be from 0.25:1 to 2:1, and will usually be from about 1:2 to 1:1.
The compositions comprising the local anesthetic, eucalyptol and any additional penetration enhancing agent employed in the subject methods will be formulated in a manner convenient for topical application. Thus, the subject compositions may be formulated as stable solutions or suspensions of the local anesthetic in eucalyptol. Alternatively, the local anesthetic and eucalyptol may be combined with one or more carrier materials to form a solution, suspension, gel, lotion, cream, ointment, aerosol spray or the like, as in known in the art.
Gel vehicles in which the subject local anesthetic and eucalyptol may be formulated to produce a topical application useful in the subject methods will physiologically acceptable and will generally comprise a solvent in combination with a thickening agent. The solvent will generally be an alkanol, such as an alcohol .
WO 98/525b7 PCT/US97108378 _ g _ or polyol, including:' ethanol, isopropanol, propylene glycol, glycerol, and the like. These alcohols and polyols may be used individually or in combination. In ' the gel vehicle, the solvent will generally be present in from about 1 to 80 weight o, more commonly 10 to 40 weight % of the topical composition.
Conventional gelling or thickening agents may be employed to provide for a formulation which can be conveniently applied to the skin. Gelling agents which have been found to be effective and are illustrative of conventionally used gelling agents for skin application include Carbomer 940 (neutralized with diisopropanolamine), neutralized polyacrylic acid, etc.
The gelling agent will be used in an amount sufficient to provide the appropriate viscosity, generally being in the range of about 0.1-5 weight percent of the formulation.
Non-ionic surfactants may be included in the compositions, where the nonionic surfactants may serve as cosolvents and epidermal penetration enhancers, in addition to the eucalyptol and any optional penetration enhancing agent described above. Conventional surfactants may be employed, which are physiologically acceptable, such as sorbitan esters, etc. When present, the nonionic surfactant will generally be present in an amount of from about 2-20 weight percent of the formulation.
The topical composition may also contain other physiologically acceptable excipients or other minor additives, particularly associated with organoleptic properties, such as fragrances, dyes, emulsifiers, buffers, cooling agents (e. g. menthol), antibiotics, stabilizers or the like. The excipients and minor additives will be present in conventional amounts ranging from about 0.001% to 50, more commonly 0.001-2%, by weight, usually not exceeding a total of 10% by weight.
Where convenient, e.g. with a gel formulation, the topical application may be covered with an occlusive dressing, which may be porous or non-porous, so as to protect the gel from mechanical removal during the period of treatment. Various inert coverings may be employed, which include the various materials which may find use in plasters, described below. Alternatively, non-woven or woven coverings may be employed, particularly elastomeric coverings, which allow for heat and vapor transport.
These coverings allow for cooling of the pain site, which provides for greater comfort, while protecting the gel from mechanical removal.
Instead of a gel, a plaster may be employed, where the composition comprising the local anesthetic and eucalyptol, and any additional penetration enhancers, may be formulated into the adhesive of the plaster. In the case of plasters, the coverings may include polyvinyl chloride, polyvinylidene chloride, (SARAN~), polyethylene, synthetic rubber, woven or nonwoven polyester fabric, etc. The local anesthetic and the eucalyptol may be combined with the adhesive with the aid of a cosolvent, or a combination of cosolvents, such as propylene glycol, glycerin, methyl salicylate, glycol ..
~_ _ salicylate, or the l ice. The particular choice of adhesive is not critical, there being a wide variety of physiologically acceptable adhesives, which can maintain the local anesthetic, eucalyptol and any additional penetration enhancing agent, in contact with the skin.
Of particular interest are the topical local anesthetic compositions described in U.S. Pat. No.
4,440,777.
In the subject methods, the topical composition comprising the local anesthetic is applied to a keratinized skin site of the host proximal to target nerves associated with the headache pain. Nerves which are commonly associated with headache pain are the occipital and supraorbital nerves. The skin site at which the composition is applied will be sufficiently proximal to the target nerves, e.g. the akin site overlies the region innervated by the target nerves, so that upon contact of the composition with the skin surface, the local anesthetic can readily reach the target nerves and exert its anti-conduction activity. Of particular interest as skin sites of topical application are the supraorbital and occipital regions.
The subject compositions will be applied to the skin site for a period of time ranging from .25 to 6 hours, usually from about .5 to 5 hours, during which time the host will experience relief from pain due to the activity of the local anesthetic on the target nerves. If headache pain recurs following removal of the topical "
composition, a new topical composition may be applied.
The process may be repeated as necessary and desired to achieve pain relief. Because of the nature of the topical local anesthetic composition employed in the subject methods, penetration of the local anesthetic is rapid.
Therefore, the patient experiences relief from the pain .
shortly after application. Usually the patient will experience at least some relief from the headache pain about .25 to 30 min following application of the topical composition, usually about .5 to 30 min following application of the topical composition.
The amount of composition applied will usually be sufficient to cover a majority of the region of skin overlying the target nerves to ensure that conduction in a sufficient percentage of the target nerves is blocked, so that the host experiences pain relief. The exact amount of topical composition that is applied may be determined empirically. For example, where the topical application is applied to the supraorbital region of the head, the amount of composition applied will be sufficient to cover at least about 50 %, more usually at least about 75 ~ of the region. For solutions, dispersions, gels, lotions, creams and the like, the composition will be spread over the region and a covering optionally applied thereto. For patches, an appropriate sized patch will be placed over the region comprising the skin site.
Conveniently, the composition may be provided in a unit dosage format, which formats are known in the art.
r i. . . w . . . .
Upon application of the topical composition, the local anesthetic rapidly penetrates the surface of the skin and blocks conduction of the target nerves which are proximal to the skin site. As a result, the patient will experience at least a partial subsidence in the intensity of headache pain, and in some cases may experience a complete cessation of pain. Thus, application of the topical local anesthetic compositions in accordance with the subject methods results in treatment of the host l0 suffering from headache pain.
The following examples are offered by way of illustration and not by way of limitation.
EXPERIMENTAL
A mixture of DEFT (N,N-diethyl-m-toluamide) and eucalyptol (1,3,3-trimethyl-2-oxabicyclo [2,2,2]-octane) was prepared in a ratio of 2:1. A sufficient amount of benzocaine free base (ca. 30% by weight) was dissolved in the mixture to produce a saturated solution of the local anesthetic.
The solution was topically applied to a female patient suffering from acute migraine without aura. The solution was applied directly to the areas of the patient's head where the supraorbital and occipital nerves are closest to the skin (the same area in which a needle would be inserted to perform regional anesthesia to these nerves). Prior to application of the solution, ~.4 -the patient rated her headache pain as "moderate°° with "moderate" nausea and "moderate°° light sensitivity.
After 15 minutes, the headache pain had subsided to a level described by the patient as "very mild."
Furthermore, the patient reported no nausea or light sensitivity. In addition, the patient did not develop any noise sensitivity, which in the past had typically became sever during previous migraine attacks.
The patient°s relief from the pain and other migraine symptoms lasted in excess of 2 hours. The patient was able to continue working following application of the topical local anesthetic solution.
This was a favorable result compared to other forms of treatment which the patient had employed previously, where, despite treatment, the patient had to stop working.
It is evident from the above results and discussion that a novel and effective method of treating headache pain in a host is provided. The nature of the topical applications employed provides for rapid penetration of the skin surface by the local anesthetic.
As a result, the patient experiences pain relief shortly after application of the composition. Furthermore, since the local anesthetic composition is topical, the method is convenient and tolerated well by patients.
a Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.
Upon application, the local anesthetic rapidly penetrates the skin surface to reach, and block conduction in, the target nerves and provide for rapid pain relief.
In various embodiments there is provided the use of a composition comprising a local anesthetic in combination with eucalyptol as a penetration enhancing agent for blocking conduction in target nerves selected from the group consisting of occipital and supraorbital nerves in the topical treatment of headache pain in a host, wherein the composition is for topical application at a keratinized skin site proximal to the target nerves.
In various embodiments there is provided the use of a local anesthetic, wherein the local anesthetic is an amine linked through a connecting group to an aromatic group, in combination with eucalyptol as a penetration enhancing agent, and with an additional penetration enhancing agent, for blocking the conduction in target nerves selected from the group consisting of occipital and supraorbital nerves in the topical treatment of headache pain in a host suffering from headache pain, wherein the local anesthetic is for topical application at a keratinized skin site proximal to the target nerves.
In various embodiments there is provided the use of a composition comprising (a) an effective amount of benzocaine, (b) eucalyptol and (c) N,N-diethyl-m-toluamide for blocking conduction in target nerves selected from the group consisting of occipital and supraorbital nerves in the topical treatment of headache pain in a host suffering from headache pain, - 5a -wherein the composition is for topical application at a keratinized skin site proximal to said target nerves.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
Methods are provided for the treatment of a host suffering from headache pain through application of topical local anesthetic compositions. The local anesthetic compositions employed in the subject methods comprise an effective amount of a local anesthetic in combination with eucalyptol as a penetration enhancing agent and provide for rapid penetration of the local anesthetic agent through a keratinized skin surface. In the subject methods, the local anesthetic composition is topically applied to a skin site proximal to target nerves associated with the headache pain. Upon application, the local anesthetic agent penetrates the skin to block conduction in the target nerves and provide pain relief to the host.
Topical compositions employed in the subject method will include a local anesthetic as the active agent. Although two or more local anesthetic agents may be present in the subject compositions, generally the subject compositions will comprise a single local anesthetic agent. The local anesthetic employed in the subject methods will be an anesthetic which, when administered in the topical formulations, rapidly penetrates a keratinized skin surface to block conduction in nerves underlying the skin surface. The local anesthetic will have a molecular weight and melting point that is compatible with transport across the keratinized skin surface. Generally, the molecular weight of the l0 local anesthetic will not exceed about 300 dal, and will more usually not exceed about 250 dal. The melting point of the local anesthetic will be less than about 100 °C.
Generally, the local anesthetic will be a compound comprised of a secondary or tertiary amine linked through a connecting group to an aromatic group. The local anesthetic will be an alkanyl compound of from about 9 to carbon atoms. Because the composition is applied topically, the local anesthetic will generally be present in the composition as a free base to promote penetration 20 of the agent through the skin surface. A large number of local anesthetics are known in the art, many of which are suitable for topical application. Suitable local anesthetics include lidocaine, butamben, butanilicaine, ethyl aminobenzoate, fomocaine, hydroxyprocaine, isobutyl p-aminobenzoate, naepaine, octacaine, parethoxycaine, piridocaine, prilocaine, procaine, risocaine, tolycaine, trimecaine, particularly ethylaminobenzoate (benzocaine).
The amount of local anesthetic present in the subject compositions will be sufficient to provide an effective amount of the agent when topically administered according to the subject methods. The precise amount of anesthetic agent present in the topical formulation will depend on the particular agent employed, but will generally range from 5 to 50 % by weight, usually from about 10 to 40 by weight.
Critical to the topical applications employed in the subject methods is eucalyptol, which serves as a penetration enhancing agent for the local anesthetic.
Eucalyptol (1,3,3-trimethyl-2-oxabicyclo[2,2,2]-octane) is the chief constituent of oil of eucalyptus and is also known as cineole and cajeputol. Eucalyptol is known in the art, having found use as an insect repellant and as a flavoring agent. The amount of eucalyptol present in the composition will range from about 10 to 80%, usually from about 10 to 50 % by weight, and more usually from about to 40 % by weight of the composition.
Optionally, the subject composition may further comprise one or more additional penetration enhancing 20 agents which work in combination with the eucalyptol to provide for rapid penetration of the local anesthetic.
Additional penetration enhancing agents will be capable of rapid penetration of the skin and be pharmaceutically acceptable, i.e. non-toxic to the host at the levels at which they are present in the composition. Examples of additional penetration enhancing agents which may find use in the subject compositions include: propylene glycol and N-methyl-2-pyrrolidone. An additional penetration enhancing agent that finds particular use in combination _.
_ g _ with eucalyptol in the subject compositions is N,N-diethyl-m-toluamide (DEET). When present, the amount of this additional penetration enhancing agent in the subject compositions will vary depending on the particular agent, as well as the Iocal anesthetic present in the composition. The amount of additional penetration enhancing agent or agents in the subject compositions will range from 10 to 80 o by weight, usually from about 30 to 60 % by weight. Generally, the ratio of eucalyptol to additional penetration enhancing agent in the subject compositions will be from 0.25:1 to 2:1, and will usually be from about 1:2 to 1:1.
The compositions comprising the local anesthetic, eucalyptol and any additional penetration enhancing agent employed in the subject methods will be formulated in a manner convenient for topical application. Thus, the subject compositions may be formulated as stable solutions or suspensions of the local anesthetic in eucalyptol. Alternatively, the local anesthetic and eucalyptol may be combined with one or more carrier materials to form a solution, suspension, gel, lotion, cream, ointment, aerosol spray or the like, as in known in the art.
Gel vehicles in which the subject local anesthetic and eucalyptol may be formulated to produce a topical application useful in the subject methods will physiologically acceptable and will generally comprise a solvent in combination with a thickening agent. The solvent will generally be an alkanol, such as an alcohol .
WO 98/525b7 PCT/US97108378 _ g _ or polyol, including:' ethanol, isopropanol, propylene glycol, glycerol, and the like. These alcohols and polyols may be used individually or in combination. In ' the gel vehicle, the solvent will generally be present in from about 1 to 80 weight o, more commonly 10 to 40 weight % of the topical composition.
Conventional gelling or thickening agents may be employed to provide for a formulation which can be conveniently applied to the skin. Gelling agents which have been found to be effective and are illustrative of conventionally used gelling agents for skin application include Carbomer 940 (neutralized with diisopropanolamine), neutralized polyacrylic acid, etc.
The gelling agent will be used in an amount sufficient to provide the appropriate viscosity, generally being in the range of about 0.1-5 weight percent of the formulation.
Non-ionic surfactants may be included in the compositions, where the nonionic surfactants may serve as cosolvents and epidermal penetration enhancers, in addition to the eucalyptol and any optional penetration enhancing agent described above. Conventional surfactants may be employed, which are physiologically acceptable, such as sorbitan esters, etc. When present, the nonionic surfactant will generally be present in an amount of from about 2-20 weight percent of the formulation.
The topical composition may also contain other physiologically acceptable excipients or other minor additives, particularly associated with organoleptic properties, such as fragrances, dyes, emulsifiers, buffers, cooling agents (e. g. menthol), antibiotics, stabilizers or the like. The excipients and minor additives will be present in conventional amounts ranging from about 0.001% to 50, more commonly 0.001-2%, by weight, usually not exceeding a total of 10% by weight.
Where convenient, e.g. with a gel formulation, the topical application may be covered with an occlusive dressing, which may be porous or non-porous, so as to protect the gel from mechanical removal during the period of treatment. Various inert coverings may be employed, which include the various materials which may find use in plasters, described below. Alternatively, non-woven or woven coverings may be employed, particularly elastomeric coverings, which allow for heat and vapor transport.
These coverings allow for cooling of the pain site, which provides for greater comfort, while protecting the gel from mechanical removal.
Instead of a gel, a plaster may be employed, where the composition comprising the local anesthetic and eucalyptol, and any additional penetration enhancers, may be formulated into the adhesive of the plaster. In the case of plasters, the coverings may include polyvinyl chloride, polyvinylidene chloride, (SARAN~), polyethylene, synthetic rubber, woven or nonwoven polyester fabric, etc. The local anesthetic and the eucalyptol may be combined with the adhesive with the aid of a cosolvent, or a combination of cosolvents, such as propylene glycol, glycerin, methyl salicylate, glycol ..
~_ _ salicylate, or the l ice. The particular choice of adhesive is not critical, there being a wide variety of physiologically acceptable adhesives, which can maintain the local anesthetic, eucalyptol and any additional penetration enhancing agent, in contact with the skin.
Of particular interest are the topical local anesthetic compositions described in U.S. Pat. No.
4,440,777.
In the subject methods, the topical composition comprising the local anesthetic is applied to a keratinized skin site of the host proximal to target nerves associated with the headache pain. Nerves which are commonly associated with headache pain are the occipital and supraorbital nerves. The skin site at which the composition is applied will be sufficiently proximal to the target nerves, e.g. the akin site overlies the region innervated by the target nerves, so that upon contact of the composition with the skin surface, the local anesthetic can readily reach the target nerves and exert its anti-conduction activity. Of particular interest as skin sites of topical application are the supraorbital and occipital regions.
The subject compositions will be applied to the skin site for a period of time ranging from .25 to 6 hours, usually from about .5 to 5 hours, during which time the host will experience relief from pain due to the activity of the local anesthetic on the target nerves. If headache pain recurs following removal of the topical "
composition, a new topical composition may be applied.
The process may be repeated as necessary and desired to achieve pain relief. Because of the nature of the topical local anesthetic composition employed in the subject methods, penetration of the local anesthetic is rapid.
Therefore, the patient experiences relief from the pain .
shortly after application. Usually the patient will experience at least some relief from the headache pain about .25 to 30 min following application of the topical composition, usually about .5 to 30 min following application of the topical composition.
The amount of composition applied will usually be sufficient to cover a majority of the region of skin overlying the target nerves to ensure that conduction in a sufficient percentage of the target nerves is blocked, so that the host experiences pain relief. The exact amount of topical composition that is applied may be determined empirically. For example, where the topical application is applied to the supraorbital region of the head, the amount of composition applied will be sufficient to cover at least about 50 %, more usually at least about 75 ~ of the region. For solutions, dispersions, gels, lotions, creams and the like, the composition will be spread over the region and a covering optionally applied thereto. For patches, an appropriate sized patch will be placed over the region comprising the skin site.
Conveniently, the composition may be provided in a unit dosage format, which formats are known in the art.
r i. . . w . . . .
Upon application of the topical composition, the local anesthetic rapidly penetrates the surface of the skin and blocks conduction of the target nerves which are proximal to the skin site. As a result, the patient will experience at least a partial subsidence in the intensity of headache pain, and in some cases may experience a complete cessation of pain. Thus, application of the topical local anesthetic compositions in accordance with the subject methods results in treatment of the host l0 suffering from headache pain.
The following examples are offered by way of illustration and not by way of limitation.
EXPERIMENTAL
A mixture of DEFT (N,N-diethyl-m-toluamide) and eucalyptol (1,3,3-trimethyl-2-oxabicyclo [2,2,2]-octane) was prepared in a ratio of 2:1. A sufficient amount of benzocaine free base (ca. 30% by weight) was dissolved in the mixture to produce a saturated solution of the local anesthetic.
The solution was topically applied to a female patient suffering from acute migraine without aura. The solution was applied directly to the areas of the patient's head where the supraorbital and occipital nerves are closest to the skin (the same area in which a needle would be inserted to perform regional anesthesia to these nerves). Prior to application of the solution, ~.4 -the patient rated her headache pain as "moderate°° with "moderate" nausea and "moderate°° light sensitivity.
After 15 minutes, the headache pain had subsided to a level described by the patient as "very mild."
Furthermore, the patient reported no nausea or light sensitivity. In addition, the patient did not develop any noise sensitivity, which in the past had typically became sever during previous migraine attacks.
The patient°s relief from the pain and other migraine symptoms lasted in excess of 2 hours. The patient was able to continue working following application of the topical local anesthetic solution.
This was a favorable result compared to other forms of treatment which the patient had employed previously, where, despite treatment, the patient had to stop working.
It is evident from the above results and discussion that a novel and effective method of treating headache pain in a host is provided. The nature of the topical applications employed provides for rapid penetration of the skin surface by the local anesthetic.
As a result, the patient experiences pain relief shortly after application of the composition. Furthermore, since the local anesthetic composition is topical, the method is convenient and tolerated well by patients.
a Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.
Claims (11)
- WHAT IS CLAIMED IS:
The use of a composition comprising a local anesthetic in combination with eucalyptol as a penetration enhancing agent for blocking conduction in target nerves selected from the group consisting of occipital and supraorbital nerves in the topical treatment of headache pain in a host, wherein said composition is for topical application at a keratinized skin site proximal to said target nerves. - 2. The use of claim 1, further comprising the use of an additional penetration enhancing agent.
- 3. The use of a local anesthetic, wherein said local anesthetic is an amine linked through a connecting group to an aromatic group, in combination with eucalyptol as a penetration enhancing agent, and with an additional penetration enhancing agent, for blocking the conduction in target nerves selected from the group consisting of occipital and supraorbital nerves in the topical treatment of headache pain in a host suffering from headache pain, wherein said local anesthetic is for topical application at a keratinized skin site proximal to said target nerves.
- 4. The use of any one of claims 1 to 3 wherein said local anesthetic is bupivacaine.
- 5. The use of any one of claims 3 to 5 wherein said additional penetration enhancing agent is N,N-diethyl-m-toluamide.
- 6. The use of a composition comprising (a) an effective amount of benzocaine, (b) eucalyptol and (c) N,N-diethyl-m-toluamide for blocking conduction in target nerves selected from the group consisting of occipital and supraorbital nerves in the topical treatment of headache pain in a host suffering from headache pain, wherein said composition is for topical application at a keratinized skin site proximal to said target nerves.
- 7. The use of claim 6, wherein said benzocaine is present in said composition in amount ranging from 20 to 40% by weight.
- 8. The use of claim 6, wherein the ratio of said eucalyptol to N,N-diethyl-m-toluamide in said composition is 1:2.
- 9. The use of any one of claims 6 to 8, wherein said composition is formulated as a gel.
- 10. The use of claim 9, wherein said gel is covered with a dressing.
- 11. The use of any one of claims 6 to 8, wherein said composition is formulated into the adhesive of a plaster.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US1997/008378 WO1998052567A1 (en) | 1995-10-30 | 1997-05-20 | Method for treating headache pain with topical local anesthetic compositions |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2283929A1 CA2283929A1 (en) | 1998-11-26 |
CA2283929C true CA2283929C (en) | 2007-02-20 |
Family
ID=22260919
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002283929A Expired - Fee Related CA2283929C (en) | 1997-05-20 | 1997-05-20 | Method for treating headache pain with topical local anesthetic compositions |
Country Status (3)
Country | Link |
---|---|
JP (1) | JP2001512415A (en) |
AU (1) | AU727736B2 (en) |
CA (1) | CA2283929C (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP7169633B2 (en) * | 2018-08-31 | 2022-11-11 | 国立大学法人山口大学 | surface anesthetic |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5748159A (en) * | 1980-09-03 | 1982-03-19 | Sharp Corp | Electronic interpreter |
US4440777A (en) * | 1981-07-07 | 1984-04-03 | Merck & Co., Inc. | Use of eucalyptol for enhancing skin permeation of bio-affecting agents |
FR2754256B1 (en) * | 1996-10-08 | 1998-12-24 | Union Pharma Scient Appl | NOVEL 1,2-DIARYLMETHYLENE DERIVATIVES, PROCESSES FOR THEIR PREPARATION, AND THERAPEUTIC USES |
-
1997
- 1997-05-20 AU AU31300/97A patent/AU727736B2/en not_active Ceased
- 1997-05-20 CA CA002283929A patent/CA2283929C/en not_active Expired - Fee Related
- 1997-05-20 JP JP52798197A patent/JP2001512415A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
JP2001512415A (en) | 2001-08-21 |
CA2283929A1 (en) | 1998-11-26 |
AU3130097A (en) | 1998-12-11 |
AU727736B2 (en) | 2000-12-21 |
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