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(12) Patent Application Publication (10) Pub. No.: US 2010/0081663 A1 Cook Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0081663 A1 Cook Et Al US 20100081663A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0081663 A1 Cook et al. (43) Pub. Date: Apr. 1, 2010 (54) METHOD OF THERAPEUTIC (60) Provisional application No. 60/900,850, filed on Feb. ADMINISTRATION OF DHE TO ENABLE 11, 2007. RAPID RELEF OF MIGRAINE WHILE MINIMIZING SIDE EFFECT PROFILE Publication Classification (75) Inventors: Robert O. Cook, Hillsborough, NJ (51) Int. Cl. (US): Stephen B. Shrewsbury, A61R 3L/4985 (2006.01) Corvallis, OR (US); Nabih N. A6IP 25/06 (2006.01) Ramadan, Lake Forest, IL (US); A6IM I5/00 (2006.01) Thomas A. Armer, Cupertino, CA (US) (52) U.S. Cl. .................................... 514/250; 128/203.15 Correspondence Address: (57) ABSTRACT MORRISON & FOERSTER LLP 755 PAGE MILL RD Pharmaceutical compositions containing dihydroergotamine PALOALTO, CA 94304-1018 (US) (DHE) and methods in which DHE is administered to patients for treatment of migraine without side effects or adverse (73) Assignee: MAP Pharmaceuticals, Inc., effects are disclosed. Methods for rapid treatment of migraine Mountain View, CA (US) with DHE are disclosed comprising: dampening the peak plasma concentration (C) and slightly delaying the peak (21) Appl. No.: 12/548,292 such as to avoid activating the dopaminergic and adrenergic receptors, while achieving sufficient active binding to the (22) Filed: Aug. 26, 2009 serotonin receptors to providerelief from migraine symptoms within a timeframe that permits rapid resolution of migraine Related U.S. Application Data symptoms. Inhaler devices suitable for the methods are dis (63) Continuation of application No. 12/069,667, filed on closed. Kits for practicing the methods of invention are dis Feb. 11, 2008. closed. Pain Relief Timepoints Placebo DHE - 0.5 mg DHE - 1.0 mg (p-value wersus placebo) (p-value wersus placebo) 1O minutes (0.019) 21% (0.068) 15 minutes (0.019) 21% (0.286) 30 minutes (0.022) 22% (0.577) (0.019) 65% (0.071) Sustained 24hrs 44% (0.060) Patent Application Publication Apr. 1 9 2010 Sheet 1 of 8 US 2010/0081663 A1 EHC–6uuO’L EHCG’O–6uu GLseinu?u97%!()%(6?O'O).VZ%||(98?’O) Oe? seinu?u ||?ºgg||(zoo)zz%(aegro).zsinou ºcc ºz.(sloo) ºgg(voo) 9.InáHI Patent Application Publication Apr. 1, 2010 Sheet 2 of 8 US 2010/0081663 A1 3.InáHz 00000},- 0000|||- 00|| (u/fd) uoeueouooHO Patent Application Publication Apr. 1, 2010 Sheet 3 of 8 US 2010/0081663 A1 g as 1. s Š cst S. SS s is:3. &3. i Ssi n 3. s C C O 3 O c) s & f5upuig Jode9e 9, Patent Application Publication Apr. 1, 2010 Sheet 4 of 8 US 2010/0081663 A1 :s: 38 8. E. S s s s s 3. s (O Š - C C O d C) O o 9 OC CO w CN c 5upus Jodeoed 9, Patent Application Publication Apr. 1, 2010 Sheet 5 of 8 US 2010/0081663 A1 O) H s i i i H -- O O O O O O 9 CO CO V CN S. (usuobe) uopenpov Jodeoed 9, Patent Application Publication Apr. 1, 2010 Sheet 6 of 8 US 2010/0081663 A1 Diagnosis and Treatment of Headache DHE (Dihydroergotamine MeSylate) Algorithm The patient WOuld enter this algorithm from b0X 460f the DHE protocol -82 Migraine Treatment Algorithm. algorithm Metoclopramide -83 10 mg IV A Begin COntinuOUSDHE 84 3 mg/1000CCIV at repetitive DHE test COSe 3-hiii., pontinuous Continuous. DHEO.5 mg/V Over 2-3 • Metoclopramide q8 enely DHE minutes hOurS PRN nausea A 89 BP 88 Return to BOX 48 in the Stable/no Migraine Treatment Algorithm DISCOntinue DHE ches,pain FIG. A Patent Application Publication Apr. 1, 2010 Sheet 7 of 8 US 2010/0081663 A1 COmmOn Side Headache persists Headache relief nO COmmOn Side effects nO COmmOn Side effects effects Metoclopramide 10 mg IV q8H PRN Metoclopramide Repeat DHE 0.5 mg 10 mg IV q8 hours NO DHE hOurS IV in 1 hour PRN nausea, then 03-04 mg/VX5 (without followed by doses q8 hours for Metoclopramide) oDHEO.5 mg IV q8 3 days hours for 2-5 dayS Return to "Migraine 94 Return to the Migraine Treatment", bOX 48 Treatment Algorithm, bOX 48 Metoclopramide Metoclopramide 10 mg IVX5 doses 10 mg IV q8 hours q8 hours PRN PRN nauSea, nausea, followed by followed by oDHE 0.75 mg IV q8 oDHE 1.0 mg IV q8 hours for 2-5 days hours for 2-5 dayS 97 Return to the Migraine Treatment Algorithm, bOX 48 A = Annotation FIG. 6B Patent Application Publication Apr. 1, 2010 Sheet 8 of 8 US 2010/0081663 A1 s s 21. O Q S S 8OH-DHE COICentration (pg/ml) US 2010/008 1663 A1 Apr. 1, 2010 METHOD OF THERAPEUTC vascular headache, i.e., arterial dilation causes pain and con ADMINISTRATION OF DHE TO ENABLE striction equals relief. Research also has now implicated a RAPID RELEF OF MIGRAINE WHILE sterile inflammation, possibly occurring in the dura mater, as MINIMIZING SIDE EFFECT PROFILE the causative factor for Vascular headpain. An unknown trig ger activates perivascular trigeminal axons, which release CROSS-REFERENCE TO RELATED vasoactive neuropeptides (substance P, calcitonin gene-re APPLICATIONS lated peptide, etc.). These agents produce the local inflam mation i.e., vasodilation, plasma extravasation, mast cell 0001. This application is a continuation of U.S. applica degranulation which cause transmission of impulses to the tion Ser. No. 12/069,667, filed Feb. 11, 2008, which claims brain stem and higher centers which in turn register as head the benefit of U.S. Provisional Application No. 60/900,850, pain (Moskowitz, M. A. (1992) Neurogenic versus vascular filed Feb. 11, 2007, the disclosures of which are incorporated mechanisms of Sumatriptan and ergot alkaloids in migraine. herein by reference in their entirety. Trends Pharmacol. Sci. 13,307-311). TECHNICAL FIELD OF THE INVENTION 0006 Migraine therapy is either prophylactic or symp tomatic. Prophylactic medication may be selected for a 0002 The present invention relates to methods for treat patient having two to four or more headaches per month, if ment of migraine. In particular, the present invention relates they are severe enough to interfere with daily activities. Beta to methods for treatment of migraine and related symptoms blockers such as propranolol (INDERAL(R) are the most while minimizing side-effects, or adverse effects, associated commonly used Other medications frequently used include with administration of medications that alleviate migraine serotonin antagonists such as methysergide maleate (SAN symptoms. More specifically, the invention relates to phar SERTR), calcium channel blockers (VERAPAMIL(R), maceutical compositions containing dihydroergotamine amytryptyline (ELAVIL(R), and ergotamine preparations (DHE) and methods in which these pharmaceutical compo with belladona alkaloids and phenobarbital. All of these sitions are administered to patients for the treatment of medications have significant side effects including sedation, migraine headaches without side effects. loss of energy and drive, dry mouth, constipation, weight gain, and gastrointestinal cramping and distress. For symp BACKGROUND OF THE INVENTION tomatic treatment, ergotamine with caffeine (CAFERGOTR) 0003 Migraine is the most common headache causing is commonly used Other medications employed for treating patients to consult a physician. According to the American migraine include isometheptene mucate (MIDRINR), non Migraine Study II, approximately 28 million people in the steroidal anti-inflammatory drugs (NSAID's such as MOT United States aged 12 and older (approximately 13 percent of RINR, NAPROXENR, etc.), dihydroergotamine and the the population) suffer from headaches that fit the medical newer triptans, such as Sumatriptan (IMITREXR), etc. When definition of migraine established by the International Head narcotics, such as FIORINAL WITH CODEINE(R) (butalbital ache Society. This corresponds to one migraine Sufferer in with codeine) are used frequently, additional hazards, includ every four U.S. households. The percentage of patients whose ing the considerable potential for rebound headaches and headaches fit the medical definition of migraine who are habituation are encountered. being diagnosed has increased compared to a decade ago. A 0007. The administration of serotonin agonists is well majority of all migraine sufferers (53 percent) characterize established for the treatment of migraine headache. The sero their pain as causing either severe impairmentor forcing them tonin agonists most widely used are the triptans, including to retreat to their beds sometimes for days at a time There have Sumatriptan, Zolmitriptan, naratriptan, rizatriptan, eletriptan, been no dramatic changes in the way physicians approach the froVatriptan and almotriptan. These compounds bind specifi treatment of migraine in the past 1.0 years. (Lipton RB et al., cally to serotonin 5-HT, receptors. To a lesser degree, Headache, (2001) 41:638-645, 646-657) ergot alkaloids such as ergotamine tartrate (referred to herein 0004. A three-item Identification of Migraine (ID as ergotamine) and dihydroergotamine mesylate (also Migraine) clinical decision rule for the diagnosis of migraine referred to as dihydroergotamine or DHE) are also used to a has been developed. (Stewart W F et al., Neurology 1994: variety of disease states, including, but not limited to the 44(6 suppl 4):S17-23.) A migraine is a type of primary head treatment of acute migraine. ache that some people get repeatedly over time Migraines are 0008 Ergotamine and DHE have very low rectal, oral, different from other headaches because they occur with sublingual and intranasal bioavailability (only 2% to 10% of symptoms such as nausea, vomiting, or sensitivity to light. In the administered dose reaches the systemic circulation). most people, a throbbing pain is felt only on one side of the These administration routes also result in relatively slow head. Migraines are classified as either “with aura' or “with onset of therapeutic efficacy, ranging from 45 minutes for out aura.” An aura is a group of neurological symptoms, intranasal to 2 hours for oral or sublingual delivery.
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