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(19) TZZ ¥ _T (11) EP 2 432 467 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/4178 (2006.01) A61K 31/4184 (2006.01) 21.02.2018 Bulletin 2018/08 A61K 31/437 (2006.01) A61K 31/439 (2006.01) A61K 31/46 (2006.01) A61K 31/4747 (2006.01) (2006.01) (2006.01) (21) Application number: 10723060.9 A61K 31/496 A61K 31/538 A61P 1/08 (2006.01) A61P 43/00 (2006.01) (22) Date of filing: 20.05.2010 (86) International application number: PCT/EP2010/056953 (87) International publication number: WO 2010/133663 (25.11.2010 Gazette 2010/47) (54) SEROTONIN 5-HT3 RECEPTOR ANTAGONISTS FOR USE IN THE TREATMENT OF LESIONAL VESTIBULAR DISORDERS SEROTONIN-5-HT3-REZEPTOR-ANTAGONISTEN ZUR VERWENDUNG BEI DER BEHANDLUNG VON VESTIBULÄREN LÄSIONSSTÖRUNGEN ANTAGONISTES DU RÉCEPTEUR 5-HT3 DE LA SÉROTONINE POUR LEUR UTILISATION DANS LE TRAITEMENT D’UN TROUBLE LÉSIONNEL VESTIBULAIRE (84) Designated Contracting States: • BROOKES G B: "The pharmacological treatment AL AT BE BG CH CY CZ DE DK EE ES FI FR GB of Menière’s disease." CLINICAL GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO OTOLARYNGOLOGY AND ALLIED SCIENCES PL PT RO SE SI SK SM TR FEB 1996 LNKD- PUBMED:8674219, vol. 21, no. 1, February 1996 (1996-02), pages 3-11, (30) Priority: 20.05.2009 EP 09305464 XP002591311 ISSN: 0307-7772 21.10.2009 EP 09305996 • MANDELCORNJEFF ET AL:"A preliminary study of the efficacy of ondansetron in the treatment of (43) Date of publication of application: ataxia, poor balance and incoordination from 28.03.2012 Bulletin 2012/13 brain injury." BRAIN INJURY : [BI] OCT 2004, vol. 18, no. 10, October 2004 (2004-10), pages (73) Proprietor: INSERM (Institut National de la Santé 1025-1039, XP008109968 ISSN: 0269-9052 et de la Recherche Médicale) • KRAUT L ET AL: "ANTI-EMETICS FOR CANCER 75013 Paris (FR) CHEMOTHERAPY-INDUCED EMESIS: POTENTIAL OF ALTERNATIVE DELIVERY (72) Inventors: SYSTEMS" DRUGS, ADIS INTERNATIONAL LTD, • CHABBERT, Christian NZ LNKD- F-34295 MONTPELLIER Cedex 05 (FR) DOI:10.2165/00003495-200161110-00003, vol. 61, • VENAIL, Frédéric no. 11, 1 January 2001 (2001-01-01), pages F-34295 MONTPELLIER Cedex 05 (FR) 1553-1562, XP009047329 ISSN: 0012-6667 • MUCHATUTA N A ET AL: "Management of (74) Representative: Icosa postoperative nausea and vomiting : focus on 83 avenue Denfert-Rochereau palonosetron", THERAPEUTICS AND CLINICAL 75014 Paris (FR) RISKMANAGE, DOVE MEDICAL PRESS LTD., NZ, vol. 5, 1 January 2007 (2007-01-01), pages 21-34, (56) References cited: XP008114229, ISSN: 1176-6336 EP-A2- 1 250 925 US-A- 4 695 578 US-A- 5 360 800 US-A- 6 063 802 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 432 467 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 432 467 B1 Remarks: Thefile contains technical information submitted after the application was filed and not included in this specification 2 EP 2 432 467 B1 Description FIELD OF THE INVENTION 5 [0001] The invention relates to serotonin 5-HT3 receptor antagonists selected from the group consisting of azasetron, tropisetron, palonosetron, lerisetron, alosetron, granisetron, dolasetron, bemesetron, ramosetron, itasetron, zacopride and cilansetron, for use in the treatment or prevention of a lesional vestibular disorder. BACKGROUND OF THE INVENTION 10 Introduction on vestibular disorders [0002] Vestibular (inner ear) disorders can cause dizziness, vertigo, imbalance, hearing changes, nausea, fatigue, anxiety, difficulty concentrating, and other symptoms, with potentially devastating effects on a person’s day-to-day 15 functioning, ability to work, relationships with family and friends, and quality of life. [0003] For example, vestibular neuritis is the first cause of hospitalisation for non-neurological vertigos. Because its aetiology is largely unknown, epidemiological studies are variable depending on the source (its incidence is believed to be between 3.5 and 50 new cases for 100000 persons/per year). In the past, either an inflammation of the vestibular nerve or labyrinthine ischemia was proposed as a cause of vestibular neuritis. Currently, a viral cause is favoured. A 20 reactivation of herpes simplex virus type 1 would explain the repetition of the vertigo crisis under such a situation. [0004] Vestibular disorders may also be involved in the majority of the fall in the elderly and their prevention became a priority. The fall in the elderly represents indeed more than 1% of the total budget of the health insurance in France (INSEE 1990). It affects in France 30% of people above 65 and 50% above 80. The fall in the elderly is involved in 2/3 of the death caused by accident above 65, and multiplies by 4 the risk of death in the following year. 25 Aetiology of vestibular disorders [0005] Although the aetiology of vestibular disorders is mostly unknown, it is widely accepted that vestibular disorders (also called vestibular deficits) constitute a vast family of conditions wherein the vestibule organ is associated. These 30 disorders may be distinguished by their putative origins. One can thus identify (1) lesional vestibular disorders and (2) non lesional vestibular disorders. 1) Lesional vestibular disorders refer to vestibular disorders wherein lesions on inner ear cells and/or vestibular nerve are present or will appear during the disorder time course. In this case, the functionality of the vestibule is 35 impaired as it can be observed using clinical functional tests (VOR, VNG). Lesional vestibular disorders include: - vestibular disorders wherein an infection inflames the inner ear and/or the vestibular nerve inducing reversible and/or irreversible damages. One example of conditions from this group is vestibular neuritis. - vestibular disorders wherein inner ear fluid levels are affected (abnormalities in the quantity, composition, and/or 40 pressure of the endolymph). These disorders usually develop lesions during the disease time course. Examples of conditions from this group are Ménière’s disease and secondary endolymphatic hydrops. They are currently associated with tinnitus and hearing loss. - Vestibular disorders induced by insults or lesions of the vestibular endorgans. Examples of said conditions are vertigo caused by local ischemia, excitotoxicity, and trauma that affect temporal bones. 45 2) Non-lesional vestibular disorders refer to vestibular disorders supported by transient and often iterative vertigo crisis wherein no lesion on inner ear cells and/or vestibular nerve can be observed. In this case, the functionality of the vestibule evaluated between the vertigo crisis using functional tests (VOR, VNG) does not differ from healthy vestibule. Non-lesional vestibular disorders include: 50 - vestibular disorders wherein debris had been collected within a part of the inner ear. This debris, called otoconia, is made up of small crystals of calcium carbonate which send false signals to the brain when they shift. Examples of said conditions are positional vertigos. - Iterative vestibular disorders of unknown origin without tinnitus or hearing loss. 55 Evaluation of the vestibule functional loss [0006] In human, morphofunctional alterations of the vestibular endorgans cannot be evaluated directly (excepted for 3 EP 2 432 467 B1 large lesions that can be detected by IRM). Rather indirect assessment methods are currently used to evaluate the loss of functionality of the vestibule. These behaviour testing methods are generally conducted at ENT clinic/hospitals. Among them, we can cite the vestibulonystagmography (VNG), and assessment of the vestibuloocculomotor reflex (VOR) using caloric or rotational tests. 5 Treatments of vestibular deficits [0007] Current treatments of vestibular deficits mainly focus on reducing the vertigo crisis using vestibuloplegic drugs, while limiting neurovegetative reactions by using anti-emetic drugs. Corticosteroids and antiviral drugs are the only 10 medications that try to limit the spread of vestibular damages in the case of vestibular neuritis (that are assumed to be due to bacterial or virus infections). Their effect remains under debate regarding the lack of aetiology in most vestibular deficits. For example, recovery after vestibular neuritis is usually incomplete. In a study of 60 patients, horizontal sem- icircular canal paresis was found in about 90% one month after the onset of symptoms, and in 80% after six months; the caloric responses normalized in only 42%. On the basis of the incidence of this condition, a substantial and permanent 15 unilateral dynamic deficit of the vestibulo-ocular reflex, which cannot be compensated for by other mechanisms, develops in approximately 4000 persons per year in the United States. This deficit leads to impaired vision and postural imbalance during walking, and especially during head movement toward the affected ear. [0008] Accordingly, there is a need for a protective or repair therapy that prevents, reduces or treats the incidence and/or severity of lesional vestibular disorders, said functional alteration of the inner ear cells and/or vestibular nerve 20 being due to an inflammation, lesions or insults of diverse origins. [0009] The Inventors surprisingly found that serotonin 5-HT3 receptors antagonists, such as ondansetron, were able to prevent or treat vestibular lesions by protecting inner ear cells and vestibular nerve from damage or degeneration. Ondansetron is known from Jellish et al. (Journal of Clinical Anesthesia 2007, 9:451-456) for reduction of postoperative nausea or vomiting after chirurgical treatment of the middle ear. In particular, ondansetron was known for preventing 25 severe vomiting after destructive surgery (such as vestibular nerve section or labyrinthectomy) in Ménière’s disease patients (Brookes GB, Clin Otolaryngol Allied Sci.
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  • WO 2007/061529 Al

    WO 2007/061529 Al

    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 31 May 2007 (31.05.2007) PCT WO 2007/061529 Al (51) International Patent Classification: GB, GD, GE, GH, GM, HN, HR, HU, ID, IL, IN, IS, JP, A61K 9/14 (2006.01) KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LV,LY,MA, MD, MG, MK, MN, MW, MX, MY, MZ, (21) International Application Number: NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, PCT/US2006/040197 SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (22) International Filing Date: 13 October 2006 (13.10.2006) (84) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (26) Publication Language: English ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT, (30) Priority Data: RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, 11/282,507 18 November 2005 (18.1 1.2005) US GN, GQ, GW, ML, MR, NE, SN, TD, TG). (71) Applicant (for all designated States except US): SCI- Declarations under Rule 4.17: DOSE PHARMA INC.