(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 27 August 2009 (27.08.2009) WO 2009/103150 Al

(51) International Patent Classification: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, A61K 31/5377 (2006.01) A61K 31/5575 (2006.01) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, A61K 31/138 (2006.01) A61K 31/08 (2006.01) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, A61K 31/382 (2006.01) A61P 25/06 (2006.01) NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, A61K 31/498 (2006.01) SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (21) International Application Number: PCT/CA2009/000182 (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (22) International Filing Date: GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, 20 February 2009 (20.02.2009) ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (25) Filing Language: English TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (26) Publication Language: English MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), (30) Priority Data: OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, 61/030,1 32 20 February 2008 (20.02.2008) US MR, NE, SN, TD, TG). (71) Applicant and Declarations under Rule 4.17: (72) Inventor: SMITH, Kevin, David [CA/CA]; 15 Varley — as to the identity of the inventor (Rule 4.17 (ϊ)) Drive, Kanata, Ontario K2K 1E7 (CA). — as to applicant's entitlement to apply for and be granted (74) Agent: FRENCH, David, J.; Miltons LLP, 700-225 Met- a patent (Rule 4.1 7(H)) 1P9 (CA). calfe Street, Ottawa, Ontario K2P — as to the applicant's entitlement to claim the priority of (81) Designated States (unless otherwise indicated, for every the earlier application (Rule 4.1 7(Hi)) kind of national protection available): AE, AG, AL, AM, Published: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, — with international search report (Art. 21(3)) EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,

(54) Title: METHOD FOR TREATING MIGRAINE HEADACHES (57) Abstract: A beta adrenergic blocking agent, preferably Timolol maleate, or ocularly compatible salts thereof, are delivered topically in the form of one or more eye drops during the interval beginning from the time and within the first 30 minutes there after when a patient first senses the onset, or potential onset, of a migraine headache. TITLE: METHOD FOR TREATING MIGRAINE HEADACHES

FIELD OF THE INVENTION [00 1] This invention relates to a procedure for treatment of migraine headaches.

BACKGROUND TO THE INVENTION [002] Migraine headaches have been a problem for mankind since time immemorial. Such headaches can last for hours and less commonly for several days. Migraine headaches can be quite severe and incapacitating.

[003] The exact cause of migraine headaches is unknown, but various hypotheses include: vascular instability, autonomic nervous system dysfunction, and dietary incompatibilities. Numerous treatments exist including serotonin agonists, NSAIDS, ergot alkaloids, narcotics, beta-adrenergic receptor blockers (beta blockers) amongst others. Typically, most of such pharmaceuticals are administered orally.

[004] A number of pharmaceuticals have been employed in the past for the treatment of migraine including beta-blocking agents intended to prevent a migraine from arising. Once a migraine has commenced, generally other drugs have been employed to ameliorate the severity of the attack. A disadvantage of the prophylactic use of beta-blocking agents is that such drugs are typically administered on a regular basis as a constant drug therapy even in the absence of indications that a migraine is developing. This is an inconvenience for patients. In some cases, side effects develop from the administration of drugs on this basis.

[005] In view of the severe burden that migraine headaches impose on individuals, any procedure for the amelioration of the severity of such event would be useful.

[006] In some patients, a warning of an impending migraine event occurs in the form of an "aura" involving modifications to vision, topical tingling or through an unarticulated intuition. US patent 5,242,949 (to Goldberg et al.) describes the treatment of migraine through the administration of a beta-adrenergic blocking agent as soon as practical when it is determined that a migraine event is likely to occur. According to this reference, the blocking agent, which can include Timolol (or its salts), is preferably administered nasally in an aqueous solution. Further, Goldberg et al, indicate that the blocking agent must be maintained at an appropriate blood concentration of for at least two hours after the onset of aura.

[007] Timolol maleate, also called "Timolol", is a non-selective beta-adrenergic receptor blocking agent. In an oral form ( e.g. Blocadren*), it is used to treat high blood pressure and prevent heart attacks, and occasionally as a prophylactic agent to prevent migraine headaches. In an ophthalmic solution ( e.g., Timoptic*) it is used to treat open-angle and occasionally secondary glaucoma by reducing aqueous humour production through blockade of the beta adrenergic receptors on the ciliary body epithelium. Timoptic* ophthalmic solution is supplied as a sterile, isotonic, buffered, aqueous solution of timolol maleate in two dosage strengths; Timoptic* 0.25% and Timoptic* 0.5%, containing 2.5mg/ml and 5mg/ml respectively. Timoptic* is applied topically as an eye drop.

[008] Timolol maleate eye drops have been prescribed as a prophylactic treatment against migraine headaches according to a report by Doctors M. Etemadifar and M. R. Abedi of the Department of Neurology, Isfahan University of Medical Science, Isfahan, Iran entitled "The preventive role of Timolol in treatment of migraine headaches", Journal of Research and Medical Sciences, VoI 10, No 5, Sept & Oct 2005. Administered in the form of a 0.5% water-based eyedrop solution, employed twice a day, this article reports success in terms of the prophylactic effect of such treatment. According to the protocol for this migraine treatment, Timolol drops were administered twice a day, one drop in the eye on the same side as the side where pain was typically occurring in the form of a headache.

[009] According to the report from this trial, the frequency of attacks per month dropped from 13.1 to 3.4 and the duration of attacks dropped from 16.4 to 2.1 hours. At the same time, the degree of severity of headaches experienced during the trial was shown to be markedly reduced.

[0010] Timolol eye drops were being administered topically in this trial as a prophylactic procedure. Accordingly, patients experienced repeated exposure to this pharmaceutical and were burdened with the constant chore of administering the drug according to a predetermined time schedule. It would be desirable to develop a treatment for migraine that is not subject to these prophylactic inconveniences. The present invention addresses such an objective.

[001 1] The invention in its general form will first be described, and then its implementation

in terms of specific testing will be detailed hereafter. These embodiments are intended to demonstrate the principle of the invention, and the manner of its implementation. The invention in its broadest and more specific forms will then be further described, and defined, in each of the individual claims which conclude this Specification.

SUMMARY OF THE INVENTION [0012] According to the invention in one aspect, a person expecting to suffer from a migraine attack is treated by the administration of a therapeutically effective amount of a pharmaceutically acceptable solution of a beta adrenergic blocking agent, more particularly Timolol maleate, or ocularly compatible salts thereof, in the form of eye drops delivered topically during the interval beginning from the time and within the first 30 minutes thereafter when a patient first senses the onset, or potential onset, of a migraine headache. The preferred 30 minute treatment window commences at the first indication of an impending migraine attack whether in the form of an actual headache experience or an aura-like anticipatory experience. The administration of this active ingredient within this time window has been found to be effective in stopping the development of a migraine headache or reducing the intensity of migraine headaches.

[0013] It is predicted that all beta adrenergic blocking agents in drop form, including compositions having non-interfering components, will be effective if used in accordance with the procedure of the invention. Table 1 summarizes brand names comprising beta adrenergic blocking agents that will be effective if used in accordance with the procedure of the invention. Table 1 - Brands and composition Brand Composition Betoptic* betoxolol Betagan* levobunolol Teoptic* metipranolol levobetaxolol carteolol Cosopt* timolol and dorzolamide Combigan* timolol and brimonidine Xalacom* timolol and latanoprost Duotrav* timolol and travoprost

*Trade-mark

[0014] According to a further preferred aspect of the invention, an optically compatible, e.g. 0.25% to 0.5%, aqueous solution of Timolol maleate is administered topically in the form of drops, the preferred dosage being one to two drops per eye and the preferred treatment being directed to both eyes.

[0015] According to another aspect of the invention, such drops may be administered repeatedly, between intervening intervals and preferably on half hour intervals, during the first two hours from the onset of a migraine headache.

[0016] It is believed and predicted that this effect, to a greater or lesser degree, but still to a therapeutically effective level, will be associated with all beta adrenergic blocking agents administered in a similar manner.

[0017] The foregoing summarizes the principal features of the invention and some of its optional aspects. The invention may be further understood by the description of the specific tests which follow.

[0018] Wherever ranges of values are referenced within this specification, sub-ranges therein are intended to be included within the scope of the invention unless otherwise indicated. Where characteristics are attributed to one or another variant of the invention, unless DESCRIPTION OF SPECIFIC TESTS [0019] At a general ophthalmology clinic, five patients with a long history of recurrent migraines were recruited to participate in a voluntary test. These patients did not have glaucoma. They were asked to treat future migraines with one drop of Timoptic* 0.5% ophthalmic solution, applied topically to both eyes at the onset of migraine or the aura of migraine, within 30 minutes of the first such indication of migraine. That is, the drops were to be delivered within the first 30 minutes thereafter when the patient first senses the onset, or potential onset of a migraine. Such administration of drops was to be repeated every half hour for up to two hours if the migraine persisted. The patients were not to use any other prophylactic or spontaneous treatment for migraine.

Patient 1 Female 49 History of migraines with classis visual aura 10 migraines over the study period. 9 migraines were stopped by one application of drops during the aura.

Patient 2 Female 2 1 History of migraines with classic visual aura 4 migraines over the study period. All responded to one application of drops at the onset of aura.

Patient 3

Male 5 1 History of migraines with classic aura. 2 migraines during study period. One migraine stopped with one application of drops. The second required a second application.

Patient 4 Female 47 History of classic migraines with aura, tension headaches, and hormonal headaches Fifteen migraines during the study period. The migraines were aborted 10 times. Patient 5 Male 38 History of classic migraines with aura. 6 migraines during the study period. All responded to one application of drops.

All patients continue using the treatment.

[0020] Although the drug administered in the these tests was Timolol maleate marketed under the trade brand: "Timoptic*", the effect is not believed to be specific to this brand. It is believed and predicted that this effect, to a greater or lesser degree, but still to a therapeutically effective level, will be associated with all beta adrenergic blocking agents administered in a similar manner. Furthermore, it is believed and predicted that this effect will similarly be associated with the topical use of any of the brands/compositions listed in

Table 1.

CONCLUSION

[0021] The foregoing has constituted a description of specific embodiments showing how the invention may be applied and put into use. These embodiments are only exemplary. The invention in its broadest, and more specific aspects, is further described and defined in the claims which now follow.

[0022] These claims, and the language used therein, are to be understood in terms of the variants of the invention which have been described. They are not to be restricted to such variants, but are to be read as covering the full scope of the invention as is implicit within the invention and the disclosure that has been provided herein. I claim:

1. A method for treatment of a person anticipating suffering from a migraine headache comprising topical administration of a therapeutically effective amount of a pharmaceutically acceptable solution of a beta adrenergic blocking agent, or an ocularly compatible salt thereof, in the form of one or more eye drops delivered to one or both eyes within 30 minutes of the first indication of said migraine.

2. The method as in claim 1 wherein the solution comprises betoxolol; levobunolol; carteolol; metipranolol; levobetaxolol; a mixture of timolol and dorzolamide; a mixture of timolol and brimonidine; a mixture of timolol and latanoprost; or a mixture of timolol and travoprost

3. The method as any one of claims 1 or 2 wherein the solution is administered to both eyes.

4. The method as in any one of claims 1to 3, wherein the eye drops are administered repeatedly thereafter in a similar manner every half hour for up to two hours in cases where the migraine persists.

5. The method as in any one of claims 1, 2, 3,or 4 comprising administration of an aqueous pharmaceutical solution of Timolol maleate, or ocularly compatible salts thereof, at a concentration of from a 0.25% to 0.5%.

6. The method as in claim 5 wherein the pharmaceutical solution is a 0.5% aqueous solution.

7. Use of a therapeutically effective amount of a beta adrenergic blocking agent or an ocularly compatible salt thereof for treatment of a migraine, wherein said beta adrenergic blocking agent or ocularly compatible salt thereof is for ophthalmic administration with 30 minutes of a first indication of said migraine. 8. The use as in claim 7 wherein the beta adrenergic blocking agent is betoxolol; levobunolol; carteolol; metipranolol; levobetaxolol; a mixture of timolol and dorzolamide; a mixture of timolol and brimonidine; a mixture of timolol and latanoprost; or a mixture of timolol and travoprost

9. Use of a beta adrenergic blocking agent or an ocularly compatible salt thereof in the manufacture of an ophthalmic solution for treatment of a migraine, wherein said solution is for ophthalmic administration within 30 minutes of a first indication of said migraine.

10. The use as in claim 9 wherein the beta adrenergic blocking agent is betoxolol; levobunolol; carteolol; metipranolol; levobetaxolol; a mixture of timolol and dorzolamide; a mixture of timolol and brimonidine; a mixture of timolol and latanoprost; or a mixture of timolol and travoprost INTERNATIONAL SEARCH REPORT International application No. PCT/CA2009/000182

A. CLASSIFICATION OF SUBJECT MATTER IPC: A61K 31/5377 (2006.01), A61K 31/138 (2006.01), A61K 31/382 (2006.01), A61K 31/498 (2006.01), A61K 31/5575 (2006.01), A61K9/08 (2006.01), A61P 25/06 (2006.01) According to International Patent Classification (IPC) or to both national classification and IPC

B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) IPC: A61K 31/5377 (2006.01), A61K 31/138 (2006.01), A61K 31/382 (2006.01), A61K 31/498 (2006.01), A61K 31/5575 (2006.01), A61K9/08 (2006.01), A61P 25/06 (2006.01)

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic database(s) consulted during the international search (name of database(s) and, where practicable, search terms used) Delphion (keyword = migraine, headache, pain, ocular, beta-blocker, topical, eye drops, metipranolol, levobetaxolol, timolol, dozolamide, brimomdme, latanoprost, travoprost, adrenergic blocking, ophthalmic); Canadian Patent Database (IPC + keywords)

C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No

Y US 5,242,949 (Goldberg et al.) 7 September 1993 (07-09-1993) 1-9 Abstract, column 2, lines 54-68, column 5, lines 5-13, claims

Y US 2003/0181354 Al (Abdulrazik) 25 September 2003 (25-09-2003) 1-9 paragraphs [0008]-[0032]; claims

Y J. Res. Med. Sd., 2005, 10(5), pp. 288-291 (Etemadifar et al.) 1-9 page 290, right column

A EP 0751766 Bl (Weg), 17 October 2001 (17-10-2001) 1-9 *entire document*

A US 5,891,885 (Caruso) 6 April 1999 (06-04-1999) 1-9 *entire document*

A US 6,685,951 (Cutler) 3 February 2004 (03-02-2004) 1-9 *entire document*

Further documents are listed in the continuation of Box C. [X ] See patent family annex.

Special categories of cited documents "T" later document published after the international filing date or priority date and not m conflict with the application but cited to understand "A" document defining the general state of the art which is not considered the principle or theory underlying the invention to be of particular relevance "X" document of particular relevance, the claimed invention cannot be "E" earlier application or patent but published on or after the international considered novel or cannot be considered to involve an inventive filing date step when the document is taken alone

"L" document which may throw doubts on priority claim(s) or which is "Y" document of particular relevance, the claimed invention cannot be cited to establish the publication date of another citation or other considered to involve an inventive step when the document is special reason (as specified) combined with one or more other such documents, such combination being obvious to a person skilled m the art "O" document referring to an oral disclosure, use, exhibition or other means "&" document member of the same patent family "P" document published prior to the international filing date but later than the priority date claimed Date of the actual completion of the international search Date of mailing of the international search report

27 May 2009 (27-05-2009) 5 June 2009 (05-06-2009) Name and mailing address of the ISA/CA Authorized officer Canadian Intellectual Property Office Place du Portage I, Cl 14 - 1st Floor, Box PCT Tung Sm 819- 934-6735 50 Victoria Street Gatineau, Quebec KlA 0C9 Facsimile No.: 001-819-953-2476 INTERNATIONAL SEARCH REPORT International application No PCT/CA2009/000182

Box No. II Observations where certain claims were found unsearchable (Continuation of item 2 of the first sheet) This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons

1 [X] Claim Nos 1-6 because they relate to subject matter not required to be searched by this Authority, namely

Claims 1-6 are directed to a method for treatment of the human or animal body by surgery or therapy which the International Search Authority is not required to search However, this Authority has carried out a search based on the alleged effects or purposes/uses of the product defined in claims 1-6

2 [ ] Claim Nos because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically

3 [ ] Claim Nos because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6 4(a)

Box No. Ill Observations where unity of invention is lacking (Continuation of item 3 of first sheet)

This International Searching Authority found multiple inventions in this international application, as follows

1 [ ] As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims

2 [ ] As all searchable claims could be searched without effort justifying additional fees, this Authority did not mvite payment of additional fees

3 [ ] As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claim Nos

No required additional search fees were timely paid by the applicant Consequently, this international search report is

restricted to the invention first mentioned in the claims, it is covered by claim Nos

Remark on Protest [ ] The additional search fees were accompanied by the applicant's protest and, where applicable, the payment of a protest fee [ ] The additional search fees were accompanied by the applicant's protest but the applicable protest fee was not paid withm the time limit specified in the invitation [ ] No protest accompanied the payment of additional search fees INTERNATIONAL SEARCH REPORT International application No Information on patent family members PCT/CA2009/000182

Patent Document Publication Patent Family Publication Cited in Search Report Date Member(s) Date

US 5242949 07-09-1993 AT 193441 T 15-06-2000 AU 675931 B2 27-02-1997 AU 3799 193A 05-10-1993 CA 2131991A1 16-09-1993 CA 2131991C 06-07-1999 DE 69328792D1 06-07-2000 DE 69328792T2 01-02-2001 DK 727986T3 30-10-2000 EP 0727986A1 28-08-1996 EP 0727986A4 25-04-1995 EP 0727986B1 31-05-2000 ES 2148222T3 16-10-2000 Fl 944236A 11-1 1-1994 Fl 944236D0 13-09-1994 GR 3034188T3 30-1 1-2000 HU 71834A2 28-02-1996 HU 9402612D0 28-1 1-1994 JP 2839207B2 16-12-1998 JP 8500329T 16-01-1996 MX 9301393A1 31-08-1994 NO 943372A 14-1 1-1994 NO 943372 DO 12-09-1994 PH 30101A 27-12-1996 PT 727986E 30-1 1-2000 WO 9317672A1 16-09-1993

US 2003181354A1 25-09-2003 IL 14792 1D O 14-08-2002 us :2008131483A1 05-06-2008

EP 0751766B1 08-01-1997 AT 2069 13T 15-1 1-2001 AT 245024T 15-08-2003 AU 733284B2 10-05-2001 AU 4982796A 11-09-1996 CA 2184077A1 31-08-1995 CA 2184077C 11-12-2007 CA 2213567A1 29-08-1996 CA 2596947A1 31-08-1995 DE 69523295D1 22-1 1-2001 DE 69523295T2 11-07-2002 DE 69629108D1 21-08-2003 DE 69629 108T2 22-04-2004 DK 0751766T3 11-02-2002 DK 0814790T3 10-1 1-2003 EP 0751766B1 17-10-2001 EP 0814790A1 07-01-1998 EP 0814790B1 16-07-2003 ES 2165910T3 01-04-2002 ES 22050 18T3 01-05-2004 JP 4173538B2 29-10-2008 JP 10500664T 20-01-1998 JP 11500729T 19-01-1999 MX 9603633A 31-01-1998 MX 9706456A 31-07-1998 PT 751766E 29-04-2002 US 5543434A 06-08-1996 US 56797 14A 21-10-1997 US 5989582A 23-1 1-1999 WO 9522965A2 31-08-1995 WO 9522965A3 21-12-1995 WO 9625925A1 29-08-1996

-/-- continued on extra sheet INTERNATIONAL SEARCH REPORT International application No PCT/CA2009/000182

Continuation of Patent Family Annex:

Patent Document Publication Patent Family Publication Cited in Search Report Date Member(s) Date

US 5891885 06-04-1999 AT 298250T 15-07-2005 AU 4806 197A 05-05-1998 CA 2267893A1 16-04-1998 DE 6973361 1D 1 28-07-2005 DE 6973361 1T2 04-05-2006 EP 0932416A2 04-08-1999 EP 0932416B1 22-06-2005 ES 2244992T3 16-12-2005 JP 2000508341 T 04-07-2000 US 5939425A 17-08-1999 US 6043244A 28-03-2000 WO 9815275A2 16-04-1998 WO 9815275A3 06-08-1998

US 6685951 B2 03-02-2004 AU 2003234292A1 10-1 1-2003 AU 2003243 178A1 10-1 1-2003 US 2003008005A1 09-01-2003 US 200301 7 175A1 23-01-2003 US 20030 17994A1 23-01-2003 US 20030229 10A1 30-01-2003 US 20031 98669A1 23-10-2003 US 2004191 178A1 30-09-2004 WO 03004002A1 16-01-2003 WO 0309071 1A1 06-1 1-2003 WO 03090798A1 06-1 1-2003