(19) & (11) EP 1 677 774 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/07 (2006.01) A61K 31/4415 (2006.01) 23.02.2011 Bulletin 2011/08 A61K 31/355 (2006.01) A61K 31/375 (2006.01) A61P 27/00 (2006.01) (21) Application number: 04791899.0 (86) International application number: (22) Date of filing: 14.10.2004 PCT/IT2004/000565 (87) International publication number: WO 2005/037262 (28.04.2005 Gazette 2005/17) (54) CITICOLINE-BASED COMPOSITION IN COMBINATION WITH VITAMINS FOR THE PREVENTION AND TREATMENT OF EYE PATHOLOGIES ZUSAMMENSETZUNG AUF CITICOLIN-BASIS IN KOMBINATION MIT VITAMINEN ZUR PRÄVENTION UND BEHANDLUNG VON AUGENERKRANKUNGEN COMPOSITION A BASE DE CITICOLINE EN ASSOCIATION AVEC DES VITAMINES POUR LA PREVENTION ET LE TRAITEMENT DE PATHOLOGIES DE L’OEIL (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR EP-A- 1 329 217 US-A1- 2001 009 678 HU IE IT LI LU MC NL PL PT RO SE SI SK TR US-A1- 2002 099 100 US-A1- 2002 164 388 US-A1- 2003 108 624 US-A1- 2004 180 085 (30) Priority: 22.10.2003 IT RM20030485 • DATABASE MEDLINE [Online] US NATIONAL (43) Date of publication of application: LIBRARY OF MEDICINE (NLM), BETHESDA, MD, 12.07.2006 Bulletin 2006/28 US; March 2000 (2000-03), CHATZISTEFANOU K I ET AL: "The role of drug treatment in children (73) Proprietor: Bausch & Lomb IOM S.p.A. with strabismus and amblyopia." XP002319128 20050 Macherio (MI) (IT) Database accession no. NLM10937461 & PAEDIATRIC DRUGS. 2000 MAR- APR, vol. 2, no. (72) Inventor: BAROZZI, Chiara 2, March 2000 (2000-03), pages 91-100, ISSN: 00040 POMEZIA (ROME) (IT) 1174-5878 • REJDAK ROBERT ET AL: "Oral citicoline (74) Representative: Banchetti, Marina et al treatment improves visual pathway function in Barzanò & Zanardo Roma S.p.A. glaucoma." MEDICAL SCIENCE MONITOR : Via Piemonte 26 INTERNATIONAL MEDICAL JOURNAL OF 00187 Roma (IT) EXPERIMENTAL AND CLINICAL RESEARCH. MAR 2003, vol. 9, no. 3, March 2003 (2003-03), pages PI24-PI28, XP002319127 ISSN: 1234-1010 Remarks: Thefile contains technical information submitted after the application was filed and not included in this specification 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 1 677 774 B1 Printed by Jouve, 75001 PARIS (FR) 1 EP 1 677 774 B1 2 Description which are initially very small and only affect the outer edges of the visual field. In this situation, the patient con- [0001] The present invention concerns a citicoline- tinues to see clearly in the centre of the field and thus based composition in combination with vitamins for the this damage is often only noticed when the optic nerve prevention and treatment of eye pathologies. More spe- 5 damage becomes considerable. When the nerve cells cifically, the invention concerns pharmaceutical and/or are completely destroyed, the loss of one’s sight is final nutritional compositions based on a choline donor com- and irreversible. pound, preferably consisting of citicoline, in combination [0006] There are some risk factors which can increase with vitamin A and vitamin B6, which are effective, also the likelihood of developing the disease, such as old age, following oral administration, in preserving and restoring 10 eye traumas, hereditary factors, systemic artery hypo- the proper structural and functional characteristics of eye tension, vascular pathologies, haematic dyscrasia, is- tissues in degenerative and non-degenerative ophthal- chaemic cardiopathologies, prolonged therapy with local mic pathologies, such as glaucoma and amblyopia, re- or systemic steroid drugs, and severe myopia. spectively. [0007] The glaucoma comes about in two different [0002] As is known, the eye is a hollow, fluid-filled or- 15 forms as regards onset and extension: a so- called open gan divided into two chambers by the crystalline lens. angle glaucoma and a so-called narrow angle glaucoma. The anterior chamber is bounded at the front by the cor- The first type, the primary open angle glaucoma, is - for nea and on the back by the iris- body ciliary-lens complex. its epidemiological features and asymptomatic course - The resulting cavity is full of a transparent liquid, the the most frequent and insidious form. It is a slow but aqueous humour, produced by ciliary processes. The 20 progressive degenerative neuropathy characterised by posterior chamber, which accounts for four-fifths of the intraocular pressure that increases gradually, without volume of the whole eyeball, is bounded at the front by there being any particular symptoms. The persistent in- the lens and at the back by the sclera-choroid- retina com- crease in pressure progressively damages the optic plex. The resulting cavity is in turn full of a transparent nerve, leading to a narrowing of the visual field and, fi- gel, the vitreous humour. 25 nally, to blindness, both being irreversible states. [0003] The retina is the nervous tissue which converts [0008] Drug treatment is usually via topical adminis- luminous stimuli into electric signals. It has a complex tration, except for the carbonic anhydrase inhibitors, structure made up of photoreceptors, bipolar cells, sup- which can also be orally administered. The drug is locally port cells and ganglion cells: The axons of the latter cells administered as an eye-drop. Drugs can only prevent line the inner surface of the retina and are bundled to- 30 glaucoma and slow down its development: thus, treat- gether into a sheath, the optic nerve, which serves to ment must start as early as possible and must never be convey electric signals to the brain’s visual areas (genic- interrupted. The active ingredients used belong to the ulate bodies and visual cortex). The optic nerve is com- classes of beta- blockers, prostaglandins, adrenergic ag- posed ofabout a million axonsand stemsfrom the eyeball onists, carbonic anhydrase inhibitors and cholinergic ag- at the level of the optic papilla. For its anatomical struc- 35 onists. tural features and complex vascular system, this is a par- [0009] As already noted, glaucoma is a chronic neu- ticularly vulnerable region which can be damaged by rodegenerative disease in which there is a selective pathologies, such as eye pressure above physiological death of the retinal ganglion cells (RGC) along with struc- limits or systemic or localised haemody- pressure above tural changes of the optic nerve head. A series of exper- physiological limits or systemic or localised haemody- 40 imental evidence suggests that in a glaucomatous eye, namic alterations. ganglion cell death is by apoptosis (programmed cell [0004] One of the clinically more important ophthalmic death) caused by the lack of trophic factors to the cell or pathologies affecting the optic nerve is, as is known, glau- by retinal ischaemic states. Other factors involved in the coma, which by itself accounts for about 15% of all cases selective death of RGCs could be cytotoxic substances of blindness in the elderly. It is an insidious disease that 45 produced by the body itself. in most cases develops slowly and without the patient [0010] Regardless of the cause and mechanism of ac- being aware of the gradual worsening of his/her vision. tion leading to RGC death, cell degeneration takes years [0005] In most cases, glaucoma is accompanied by a and there is thus the time available for neuroprotective continuous increase in intraocular pressure which devel- drug therapy to prevent RGC death. Therefore, the aim ops following an obstacle to the flow of the aqueous hu- 50 of a neuroprotective treatment, which must be comple- mour and the resulting accumulation of liquid. After a mentary to and not replace the eye- drops reducing ocular while there is a compression or squeezing of the optic pressure, is that of directly acting on the progressive de- nerve, with the resulting damage or death of the nerve generation of the cells and of the nerve fibres conveying fibres. Damage to the optic nerve leads to a gradual al- electric impulses from the retina to the brain, by making teration of the visual field, which tends to gradually narrow 55 them more resistant to various damaging stimuli, recov- until it finally disappears. If the optic nerve fibres are dam- ering them from a suffering state and stimulating their aged, then the visual field will start to have areas where function. vision is no longer possible, referred to as scotomas, [0011] Another eye pathology requiring treatment as 2 3 EP 1 677 774 B1 4 early as possible to guarantee some effect is amblyopia. natural origin and composed of ribose, cytosine, pyro- This may be defined as a visual deficit in one or, more phosphate and choline, formed starting from phospho- rarely, both eyes that is not explained by pathologies choline and cytidine-5-triphosphate in a reversible reac- identifiable by the oculist, and which cannot be ascribed tion catalysed by CTD-choline transferase (CT). Phos- to organic lesion ascertainable via a physical examina- 5 phocholine is in turn obtained by phosphorylation of tion of the eye. Usually, an eye suffering from amblyopia choline, and cytidine- 5-triphosphate is obtained by phos- is called a "lazy eye" for the very reason that it does not phorylation of cytidine. present a specific pathology, but that its function has not [0017] The biological importance of CDP-choline lies developed completely.