Ozonised oil for use in the prevention and / or treatment of age-related macular degeneration

Abstract

The present invention refers to an ozonised oil for use in the prevention and / or treatment of age-related macular degeneration (AMD). Said ozonised oil is particularly effective in the treatment and / or prevention of neovascular AMD.

Description

[0001] OZONISED OIL FOR USE IN THE PREVENTION AND / OR TREATMENT

[0002] OF AGE-RELATED MACULAR DEGENERATION

[0003] Field of the invention

[0004] The present invention refers to an ozonised oil for use in the prevention and / or treatment of age-related macular degeneration (AMD) . Prior art

[0005] Age-related macular degeneration (AMD) i s one of the maj or causes of visual impairment . It is estimated that around 200 million people worldwide were af fected by AMD in 2020 and that AMD suf ferers could reach 300 million by 2040 , thus generating a serious public health problem with substantial social-economic implications (Wong WL et al . Global prevalence of age-related macular degeneration and disease burden proj ection for 2020 and 2040 : a systematic review and meta-analysis . Lancet Glob Health . 2014 ; 2 : el 06-el 16 ) .

[0006] AMD has widespread ef fects on quality of li fe . Studies show that patients with AMD report greater stress , lower personal satis faction, lower activity levels , and a higher incidence of depressive syndromes than similarly aged individuals without AMD (Brody BL et al . Depression, visual acuity, comorbidity, and disability associated with age-related macular degeneration . Ophthalmology 2001 ; 108 : 1893-901 ) .

[0007] AMD has also been associated with an increased ri sk of functional disability in the elderly ( Gopinath B et al . Age-related macular degeneration and 5-year incidence of impaired activities of daily living . Maturitas 2014; 77: 263-66) ; a direct relationship between AMD and an increased risk of falls and other injurious falls has also been demonstrated (Wood JM et al. Risk of falls, injurious falls, and other injuries resulting from visual impairment among older adults with age-related macular degeneration. Invest Ophthalmol Vis Sci 2011; 52 : 5088-92) .

[0008] AMD is a pathology with multifactorial aetiology. Based on current scientific knowledge, several risk factors can be identified, first and foremost the age, but also genetics, smoking, obesity, overweight, hypertension, cardiovascular diseases, consumption of dietary fats and of alcohol.

[0009] The aforementioned pathology affects the macular region of the retina, causing progressive loss of central vision (Lim LS et al. Age-related macular degeneration. Lancet 2012; 379: 1728-38) .

[0010] In the initial stages, AMD produces clinical signs such as drusen (deposits of protein-lipid material found between the basement membrane of the retinal pigmented epithelium (RPE) and the inner collagen layer of Bruch's membrane) and RPE abnormalities.

[0011] In advanced stages, the aforementioned pathology can be distinguished into:

[0012] - Neovascular AMD (also known as wet or exudative AMD) , in which a neoformation of abnormal vessels occurs in the fundus of the eye, or

[0013] - Non-neovascular AMD (also known as atrophic, dry or non-exudative AMD) .

[0014] Advanced AMD causes loss of central visual acuity, which leads to severe and permanent visual impairment as well as sometimes legal blindness with consequent impact on the patient's quality of life and functional independence .

[0015] In the work by Sagai et al. 2011 (Med Gas Res. 2011 Dec 20:1:29. Mechanisms of Action Involved in Ozone Therapy : Is healing induced via a mild oxidative stress? Masaru Sagai, Velio Bocci) a possible role in AMD of ozone therapy, administered in gaseous form by blood transfusion, is mentioned, however with modest results.

[0016] The topical application of ozonised oil is known to treat certain pathologies affecting the anterior segment of the eye, such as corneal ulcers (Ozone therapy application in different ophthalmologic diseases : study of 59 cases (Aplicacidn de la ozonoterapia en di f erentes enfermedades oftalmoldgicas: estudio de 59 casos) , Ivan Vigna, Silvia Menendez-Cepero, Recvet, vol. II, no.11, 1 November 2007; Ozonoterapia como tratamiento coadyuvante en la ulcera corneal grave bacteriana, Duperet-Carva j al Danay, Rev Inf Cien, Vol. 100, No. 3 (2021) ) , which however are profoundly different from pathologies which affect the fundus of the eye and, therefore, selectively the posterior segment, such as AMD.

[0017] Despite numerous ongoing studies, to date there is no effective therapy for either initial maculopathy or advanced non-neovascular maculopathy, the latter being the far more widespread form of advanced AMD.

[0018] Neovascular AMD, on the other hand, is now successfully treated by means of anti-VEGF drugs, inhibiting vascular endothelial growth factor, which is produced in the fundus o f the eye due to the hypoxic condition correlated to AMD .

[0019] However, anti-VEGF therapy i s very invasive , as it is administered by means of intravitreal inj ections that must be repeated according to reference protocols , adapted to the individual case . In addition, this treatment has several side ef fects , even serious , such as corneal lesions and endophthalmitis . The frequency with which these treatments must be carried out represents the greatest criticality for patients with AMD .

[0020] The need is therefore felt to find a therapeutic treatment for age-related macular degeneration that overcomes the drawbacks of the known art and that i s ef fective , non-invasive and that promotes high compliance by the patient . In particular, the need is felt to increase the ef ficacy of known treatments , thus allowing the frequency thereof to be reduced as much as possible .

[0021] The need to prevent the pathology is also felt . Summary of the invention

[0022] The Applicant has found that the administration o f an ozonised oil to a patient is extremely ef fective in the prevention and treatment of both early stage and late stage AMD (neovascular ( or wet ) AMD and non- neovascular ( or dry) AMD) .

[0023] In particular, the Applicant has found that the administration of ozonised oil cons iderably reduces the need to administer, by means of intravitreal inj ections , anti-VEGF antibodies , since it increases the intensity and duration of the ef ficacy, with considerable advantages in terms of the patient' s well-being and compliance , as well as economic savings .

[0024] Therefore , according to a first aspect , the present invention refers to an ozonised oil for use in the prevention and / or treatment of age-related macular degeneration (AMD) .

[0025] Preferably, the age-related macular degeneration i s chosen from neovascular ( or wet ) AMD, non-neovascular ( or dry) AMD, and early stage AMD, more preferably neovascular ( or wet ) AMD .

[0026] The present invention also re fers to a method for the prevention and / or treatment of age-related macular degeneration comprising administering an ozonised oil to a human or animal (non-human) mammal in need thereof . According to a preferred aspect of the present invention, said human or animal subj ect is treated with a conventional therapy for the prevention and / or treatment of AMD, more preferably neovascular AMD, such as for example anti-VEGF intravitreal inj ections , or laser therapy . In particular, the ozonised oil may be administered before, after, during and / or alternately with said conventional therapy, e . g . anti-VEGF inj ections .

[0027] Preferably, the age-related macular degeneration i s chosen from neovascular ( or wet ) AMD, non-neovascular ( or dry) AMD, and early stage AMD, more preferably neovascular ( or wet ) AMD .

[0028] Preferably, the ozonised oil is for oral administration .

[0029] Preferably, the ozonised oil has a content o f ozonides from 500 to 1500 meq Cb / kg, more preferably from 600 to 1400 meq Cb / kg, still more preferably from 700 to 1300 meq Cb / kg, still more preferably from 1100 to 1300 meq Cb / kg, most preferably 1200 meq Cb / kg .

[0030] The content of ozonides can be measured according to techniques known in the f ield, for example by the method for determining the number of peroxides described in Regulation (EEC) No . 2568 / 91 of 11 July 1991 concerning the characteristics of olive oils and olivepomace oils and the methods related thereto (Annex I I I ) .

[0031] In accordance with the present invention and appended claims , the expression "ozonised oil" means : a vegetable oil that has undergone an ozonising process ; an unsaturated fatty acid, preferably having a number of carbon atoms from 8 to 30 , more preferably from 16 to 20 , that has undergone an ozonising process ; an ester o f an unsaturated fatty acid, preferably having a number of carbon atoms from 8 to 30 , more preferably from 16 to 20 , which may be a monoester, diester or triester, with an alcohol or a polyol , in particular glycerol , that has undergone an ozonising process ; or mixtures thereof .

[0032] Preferably, the at least one ozonised oil is chosen from : at least one vegetable oil that has undergone an ozonising process ; at least one unsaturated fatty acid that has undergone an ozonising process ; at least one monoester of an unsaturated fatty acid that has undergone an ozonising process ; and mixtures thereof ; more preferably at least one vegetable oil that has undergone an ozonising process.

[0033] Preferably, the at least one vegetable oil that has undergone an ozonising process is chosen from: sunflower oil, peanut oil, argan oil, olive oil, grapeseed oil, jojoba oil, soybean oil, corn oil, palm oil, cottonseed oil, rapeseed oil, coconut oil, castor oil, linseed oil, borage oil, evening primrose oil, and mixtures thereof, more preferably sunflower oil, peanut oil, argan oil, grapeseed oil, jojoba oil, soybean oil, corn oil, palm oil, cottonseed oil, rapeseed oil, coconut oil, castor oil, linseed oil, borage oil, evening primrose oil, and mixtures thereof, even more preferably sunflower oil and / or peanut oil, most preferably sunflower oil.

[0034] Preferably the at least one unsaturated fatty acid that has undergone an ozonising process has a number of carbon atoms from 8 to 30, more preferably from 16 to 20, even more preferably 18.

[0035] Preferably, the at least one unsaturated fatty acid has from one to six double bonds in the carbon chain, more preferably from one to three double bonds in the carbon chain.

[0036] Preferably the at least one fatty acid is monounsaturated (and thus has only one double bond in the carbon chain) .

[0037] Preferably, the at least one fatty acid is oleic acid .

[0038] Preferably, the at least one monoester of an unsaturated fatty acid, which has undergone an ozonising process, is obtained by esterifying the aforesaid unsaturated fatty acid as described above, the monoester having undergone an ozonising process .

[0039] Preferably, the at least one monoester o f unsaturated fatty acid is obtained by esteri fying the aforesaid unsaturated fatty acid with an aliphatic primary alcohol having only one -OH (monovalent ) group, more preferably ethanol .

[0040] Preferably, the at least one monoester o f unsaturated fatty acid is ethyl oleate .

[0041] Preferably, the at least one ozonised oil is substantially free of antioxidant agents .

[0042] Preferably, the at least one ozonised oil is obtained from an ozonising process which uses highly puri fied gaseous oxygen for the introduction of oxygen .

[0043] With regard to oral administration, the at least one ozonised oil may be in the form of an ozonised oi l as such or a formulation for oral administration comprising the at least one ozonised oil and at least one pharmaceutically acceptable excipient .

[0044] The formulation for oral administration may be in a form chosen from oil , syrup, tablets and capsules , more preferably capsules .

[0045] Preferably, the tablets are gastroresistant .

[0046] Preferably, the capsules are chosen from soft gelbased capsules , and gastroresistant capsules , more preferably gastroresistant capsules .

[0047] Preferably, the composition of the gastroresistant capsules comprises at least one coating agent , preferably hydroxypropyl methylcellulose , and at least one gelling agent , preferably chosen from pectin, gel lan gum, and mixtures thereof . The formulation in the capsules may be in liquid form or in solid form, preferably solid, even more preferably in powder or granular form .

[0048] Preferably, the capsules each contain from 50 to 200 mg, more preferably from 140 to 160 mg, most preferably 150 mg, of ozonised oil .

[0049] The at least one pharmaceutically acceptable excipient is selected from those commonly used for formulations for oral administration . It should be noted that such excipients preferably do not include any preservative or antioxidant agents . In fact , such agents interact with ozonised oil , as they are subj ect to oxidation by the ozonide groups .

[0050] Regarding the dosage of oral administration, it is variable , depending on the condition of the patient and the progress of the pathology .

[0051] Preferably, the oral administration of the ozonised oil is carried out by the administration of a quantity of ozonised oil from 75 to 1500 mg per day per 70 kg o f body weight , more preferably from 150 to 1200 mg per day per 70 kg of body weight , still more preferably from 200 to 900 mg per day per 70 kg of body weight , most preferably from 450 to 700 mg per day per 70 kg of body weight .

[0052] Preferably, the oral administration of the formulation is carried out once or twice a day, even more preferably twice a day .

[0053] Preferably, the oral administration of the ozonised oil is carried out for a period of at least one month, more preferably from one month to 3 years , still more preferably from 2 months to 14 months , most preferably from 5 months to 12 months .

[0054] The oral administration in the form of capsules of the ozonised oil for the use of the invention is particularly advantageous for the simplicity of administration and the possibility of delivering and releasing oxygen directly into the tissue and cells concerned, increasing the ef ficacy and duration of the ef fect .

[0055] Preferably, the formulation is administered orally in association with at least one conventional therapy for the prevention and / or treatment of AMD, more preferably neovascular AMD, such as for example anti- VEGF intravitreal inj ections , or laser therapy ( to slow the progression of drusen) . In particular, the ozonised oil may be administered before , after, during and / or alternately with said conventional therapy, e . g . anti- VEGF inj ections . This advantageously allows to reduce the frequency of administration of the conventional therapy .

[0056] Retinal cells are characteri zed by a high consumption of oxygen, which is used for energy production by oxidation processes within mitochondria . Reactive oxygen species (ROS ) , such as superoxide anion, hydrogen peroxide , and hydroxyl radical are the standard product of cellular metabolism within mitochondria, but enzymatic reactions and exogenous factors , such as smoking or an unbalanced diet , are sources of ROS . Under physiological conditions , ROS are neutrali zed by an antioxidant system, and, among others , by antioxidant enzymes such as superoxide dismutase or glutathione .

[0057] In case of disorders of the cel lular metabolism or insuf ficiency of the antioxidant system, an excess o f ROS can be produced, and an unbalanced production of the latter is a cause of oxidative stress .

[0058] During oxidative stress , oxidation of molecules such as proteins , lipids , carbohydrates and nucleic acid occurs , which can lead to damage and mal function thereof ; oxidative stress contributes to the damage of the cell structures and cell death . The processes involved are mainly focused on the mitochondria, where the production of excess ROS induces a decrease in ATP production in favour of the generation of ROS , which are the cause o f oxidation of lipids and proteins , components of the mitochondrial membrane . Subsequently, mitochondrial breakdown, energy deficiency, lipid and protein mal function, and cell membrane damage ultimately induce cell death .

[0059] High oxygen requirements , high amounts o f polyunsaturated fatty acids and low levels of antioxidant enzymes make the retina - as well as the nervous system - extremely sensitive to oxidative stress .

[0060] Loss of retinal neurons causes vi sion disturbances and blindness ; therefore , prevention of neuronal death in the retina is crucial .

[0061] The RPE is crucial for the survival of retinal cells; RPE cells (I) transport nutrients from the blood vessels to the photoreceptors, (II) transport the end products of metabolism into the blood, (III) phagocytose the outer segments of the photoreceptors (POS) , which are constantly eliminated by the rods and cones, (IV) reisomerise again the trans-retinal into 11-cis-retinal , (V) produce growth factors and (VI) contribute to the formation of the blood-retinal barrier. Any disturbance of any of these functions can lead to retinal cell death.

[0062] RPE and photoreceptors are post-mitotic, nonproliferating cells; therefore, the accumulation of damage within the cell and of final metabolic products naturally increases with age. A high concentration of oxygen due to increased energy demand and irradiation contributes to the formation of ROS and promotes oxidative activity. ROS and POS are rich in polyunsaturated fatty acids, which are prone to oxidation, this feature, in the context of EPR, increases the accumulation of lipofuscin, a product of the oxidation of unsaturated fatty acids. These aggregates impede the functioning of the RPE, which further affects the proper functioning of the photoreceptors. The phagocytic activity of the RPE, which decreases with age, induces the deposition of drusen below the RPE cells, which further translates into a phlogistic response. Chronic oxidative stress that induces cell death also causes local inflammation (the so-called para-inflammation) , supporting tissue repair and restoring homoeostasis . However, i f the oxidative stress is constant , the inflammatory response becomes chronic and causes tissue damage . Oxidative stress also favours angiogenesis , for example through ROS derived from NADPH oxidase activity or through the accumulation of advanced glycation end products that stimulate the production o f RPE and VEGF, promoting the neovasculari zation characteristic of wet AMD .

[0063] Without wishing to be bound by any theory, it i s hypothesi zed that the administration of ozonised oil would activate the antioxidant response aimed at neutrali zing the oxidant species with a consequent activation of the antioxidants . It is believed that the antioxidant response is activated about 9 hours after taking the ozonised oil . This latency period is necessary for the body to activate the Antioxidant Responsive Elements (ARE ) system represented by genes that code for antioxidant enzymes and oligoprotides ( e . g . reduced glutathione consisting of the amino acids glutamic acid, cysteine and glycine ) . It is believed that the antioxidant response to the administration of ozonised oil is not due to the s imple mobili zation of already present endogenous antioxidants but to the production o f new antioxidant proteins that by their nature have very long hal f-lives . Therefore , the benefit acquired from the administration of ozonised oil is stable over time .

[0064] With particular reference to the treatment and / or prevention of neovascular AMD, it is believed that ozoni zed oil is able to increase the tissue availability of oxygen, blocking the production of the endothelial vascular growth factors and thus stopping the phenomenon of neovasculari zation . In particular, it is believed that the increased tissue availability of oxygen induced by the ozonised oil blocks the activation of Hypoxia Inducible Factor (HI F) , the main activator of vascular endothelial growth factors (VEGF) with a pro-angiogenic action .

[0065] Description of the figures

[0066] Figure 1 shows images obtained by three-dimens ional optical coherence tomography ( OCT ) referred to patient 1 .

[0067] Figure 2 shows images obtained by computer analysis of the visual field by Humphrey perimetry referred to patient 2 .

[0068] Figure 3 shows images obtained by two-dimens ional optical coherence tomography ( OCT ) referred to patient

[0069] 3 .

[0070] Figure 4 shows images obtained by two-dimens ional optical coherence tomography ( OCT ) referred to patient

[0071] 4 .

[0072] Figure 5 shows images obtained by two-dimens ional optical coherence tomography ( OCT ) referred to patient 5 .

[0073] Figure 6 shows images obtained by slit lamp and digital photograph of the Fundus Oculi referred to patient 6 . Figure 7 shows images obtained by two-dimensional optical coherence tomography ( OCT ) referred to patient 7 .

[0074] Detailed description of the invention

[0075] The present invention will now be further illustrated by means of some experimental tests in vi vo as reported below .

[0076] EXAMPLE

[0077] A clinical study was conducted to evaluate the ef ficacy of the ozonised oil according to the invention as a complementary treatment of the age-related macular degeneration .

[0078] The study was conducted on 7 patients with neovascular AMD, who were administered, in the form o f a gastroresistant capsule , an ozonised oil orally according to the invention, as a treatment additional to a traditional treatment that included intravitreal inj ections of anti-VEGF monoclonal antibody ( commercial formulations Avastin® (bevaci zumab ) or Lucentis® ( ranibi zumab ) ) on a monthly basis . In all patients , the intravitreal inj ections of anti-VEGF antibody were discontinued during the administration of ozonised oil .

[0079] The gastroresistant capsule contained a solid granule formulation comprising 150 mg ozonised sunflower oil having a content o f ozonides of 1200 meg Ch / kg and pharmaceutically acceptable excipients . The gastroresistant capsule was a conventional gastroresistant capsule based on hydroxypropyl methylcellulose, pectin and gellan gum.

[0080] The status of the pathology was assessed prior to administration of the ozonised oil (TO) and after a few months of treatment (Tl) , which vary from patient to patient as described below. Since, as indicated above, during the period of administration of ozonised oil the treatment with anti-VEGF was discontinued, the clinical differences observed between Tl and TO are exclusively attributable to the treatment with ozonised oil.

[0081] Results

[0082] Patient 1

[0083] Male, 75 years old, weight 84 kg. Previous strong and frequent exposure to sunlight in the absence of personal protective equipment (sunglasses) . Diagnosis of severe and progressive AMD due to worsening visual defect with bilateral central and peripheral scotoma. The patient was treated with ozonised oil with a dosage of 2 capsules (caps.) per day divided into two administrations per day (1x2) 12 hours apart, increased after the first two months to 6 caps, per day divided into two administrations per day (3x2) 12 hours apart for three months .

[0084] After treatment, a halt in the progression of the pathology and partial recovery of the visual function were observed. A cross over was carried out with discontinuation of the treatment with ozonised oil.

[0085] After 2 months of discontinuation, the patient reported a new progressive worsening of the visual function with resumption of the pathology progression. The treatment was then resumed at a dose of 6 caps, per day divided into two administrations per day (3x2) 12 hours apart. The treatment was continued for 6 months with total halt of the pathology progression and partial recovery of the visual function.

[0086] The fundus of the eye was analysed before the start of the treatment (TO) and at the end of the treatment (i.e. at the end of the final 6 months) (Tl) by means of three-dimensional optical coherence tomography (OCT) . The results obtained are reported in Figure 1. OCT 3D highlights that the noticeable area of vascular neoproliferation detected in TO (white and red colours, mainly in the centre) has visibly regressed in Tl after treatment (blue, green, yellow colours) . The colours indicate the height of the plane of neo-proliferation with respect to the average height of the plane of the fundus of the eye. Patient 2 Female, 63 years old, weight 72 kg, smoker. Diagnosis of progressive AMD for 2 years with severe visual impairment. Computerised assessment of the visual field was carried out before (TO) and after (Tl) 8 months of treatment with ozonised oil with a dosage of 4 caps, per day divided into two doses per day (2x2) 12 hours apart. The results obtained by computerised analysis of the visual field (Humphrey perimeter) are reported in Figure 2. The results obtained indicate that the severe visual deficit detected in TO (black and grey areas) is corrected after treatment T with the persistence of only the physiological blind spot corresponding to the fovea and a grey halo of surrounding visual deficit. Patient 3

[0087] Female 72 years old, weight 68 Kg. AMD diagnosis 1 year ago, with central lesion and multiple lifts. Treatment carried out with ozonised oil at a dosage of 4 caps, per day divided into two administrations per day (2x2) 12 hours apart, for 6 months. The two-dimensional OCT results were compared before (TO) and after (Tl) treatment (Figure 3) . The results of the 2D OCT indicate that the noticeable multiple degenerative alteration observable before treatment (TO) has significantly regressed after treatment in Tl. At the same time, the patient reported the halt of the progression of the visual deficit and significant improvement in visual function . Patient 4

[0088] Female, 59 years old, weight 64 kg, smoker since the age of 15 (20 cigarettes per day) . She reported a progressive loss of vision with reading difficulties: AMD diagnosis. Treatment initiated with ozonised oil with a dosage of 4 caps, divided into two administrations per day (2x2) 12 hours apart per day for 8 months. Two-dimensional OCT carried out before (TO) and after (Tl) the treatment. The results obtained are reported in Figure 4. The results obtained indicate that the noticeable vascularized neoformed lesion detected in TO is almost completely regressed after treatment. The patient reported the halt of the progression of the pathology and significant improvement in visual function. Patient 5

[0089] Male, 60 years old, weight 74 kg, smoker. One year ago, AMD was diagnosed with progressive visual function deficits. Treatment initiated with ozonised oil with a dosage of 4 capsules per day divided into two administrations per day (2x2) 12 hours apart for 10 months. 2D comparative OCT carried out before (TO) and after (Tl) the treatment. The results obtained are reported in Figure 5. Two-dimensional OCT indicates that the main rounding neovascular lesion and the more fringed and irregular lateral secondary lesions detected at TO are almost completely regressed after treatment. The patient reported the halt of the progression of the pathology and improvement of vision. Patient 6

[0090] Female 72 years old, weight 72 kg, former smoker. AMD diagnosis for 3 years. Treatment initiated with ozonised oil at a dosage of 4 caps, per day divided into two administrations (2x2) per day 12 hours apart, for 10 months. Comparative evaluation was carried out by digital photography of the Fundus Oculi before (TO) and after (Tl) the treatment. The results obtained, by means of a slit lamp and digital photography of the Fundus Oculi, are reported in Figure 6. It can be seen how the noticeable situation of neo-vascularization with angiectasis detected in TO is strongly attenuated in T1 after treatment. During treatment, the patient reported the halt of the progression of the pathology and improvement of vision. Patient 7

[0091] Male, 63 years old, weight 82 kg, former smoker. Previous exposure to sunlight for professional reasons (fisherman) in the absence of personal protective equipment (sunglasses) . AMD diagnosis one year ago. Treatment carried out with ozonised oil with a dosage of 4 caps, per day divided into two administrations per day 12 hours apart for 8 months. Two-dimensional OCT comparative evaluation was carried out before (TO) and after (Tl) treatment. The results obtained are reported in Figure 7. The results obtained reveal before treatment (TO) the presence of an evident neo-vascularised degenerative lesion before treatment, with multiple neo- angiogenic foci and detachment of the retinal tissues. After treatment (Tl) the lesions have almost totally regressed with the persistence of a minimal lesion located posteriorly to the left of the fovea but barely detectable. There is also a general disappearance of the edemogenic phenomena of the retinal tissues. During treatment, the patient reported a halt in the progression of the pathology and significant improvement of vision. The following Table 1 summarizes the therapy modalities for each patient. Table 1 - Summary diagram of the therapies carried out on each patient .

[0092] General Results

[0093] All seven patients examined underwent objective assessment of the visual function both by means of visual acuity tests (optometric chart) and by means of Amsler grid tests. The latter test is the most specific and indicated for the early diagnosis and assessment of the rate of progression of AMD . The reference ophthalmologist detected an average improvement in visual acuity by 2 tenths with speci fic reference to the eye af fected by the maj or AMD lesion . During the Amsler grid test the ophthalmologist detected a 30-50% decrease in the following pathological parameters : blind areas with inability to visuali ze the lines of the grid, number of broken or de formed lines , blurred lines , presence o f blind areas ( light or dark) , inability to visuali ze with sharp margins and clearly the central black point of the grid .

[0094] In addition, no side or undesired ef fects that can be correlated to the administration of ozonised oil were found in any of the seven patients .

[0095] Conclusions

[0096] The results obtained in the patients examined indicate that the oral treatment with ozonised oils ef fectively contributes to the halt of progression and also to the regression o f AMD in the absence of s ide ef fects . In particular, the results demonstrate that the ozonised oil is able to stop the progression of the disease even in the absence of further intravitreal administrations of anti-VEGF, thus allowing to signi ficantly reduce the need to administer anti-VEGF by means of intravitreal inj ections . This result represents a signi ficant advantage for the patient , both in terms of non-invasiveness of treatment and cost reduction, given the high costs of anti-VEGF monoclonal antibodies .

Claims

CLAIMS1. Ozonised oil for use in the prevention and / or treatment of age-related macular degeneration (AMD) .

2. Ozonised oil for use according to claim 1, wherein the age-related macular degeneration is chosen from neovascular AMD, non-neovascular AMD, and early stage AMD, preferably neovascular AMD.

3. Ozonised oil for use according to claim 1 or 2, wherein said ozonised oil is for oral administration.

4. Ozonised oil for use according to any one of the previous claims, wherein said ozonised oil has a content of ozonides from 500 to 1500 meg 02 / kg, preferably from 600 to 1400 meq 02 / kg, more preferably from 700 to 1300 meq 02 / kg, even more preferably from 1100 to 1300 meq 02 / kg, most preferably 1200 meq 02 / kg.

5. Ozonised oil for use according to any one of the previous claims, wherein said ozonised oil is chosen from: at least one vegetable oil that has undergone an ozonising process; at least one unsaturated fatty acid that has undergone an ozonising process; at least one monoester of an unsaturated fatty acid, that has undergone an ozonising process; and mixtures thereof; preferably at least one vegetable oil that has undergone an ozonising process.

6. Ozonised oil for use according to claim 5, wherein said at least one vegetable oil that has undergone an ozonising process is chosen from: sunflower oil, peanut oil, argan oil, olive oil, grapeseed oil, jojoba oil, soybean oil, corn oil, palm oil, cottonseed oil, rapeseed oil, coconut oil, castor oil, linseed oil,borage oil, evening primrose oil, and mixtures thereof, preferably sunflower oil, peanut oil, argan oil, grapeseed oil, jojoba oil, soybean oil, corn oil, palm oil, cottonseed oil, rapeseed oil, coconut oil, castor oil, linseed oil, borage oil, evening primrose oil, and mixtures thereof, more preferably sunflower oil and / or peanut oil, most preferably sunflower oil.

7. Ozonised oil for use according to claim 5, wherein said at least one unsaturated fatty acid is oleic acid .

8. Ozonised oil for use according to any one of the previous claims, wherein said at least one ozonised oil is in the form of an ozonised oil as such or a formulation for oral administration comprising said at least one ozonised oil and at least one pharmaceutically acceptable excipient.

9. Ozonised oil for use according to claim 8, wherein said formulation for oral administration is in a form chosen from oil, syrup, tablets and capsules, preferably capsules, even more preferably gastroresistant capsules.

10. Ozonised oil for use according to claim 9, wherein said capsules each contain from 50 to 200 mg, preferably from 140 to 160 mg, more preferably 150 mg, of ozonised oil.

11. Ozonised oil for use according to any one of claims 3 to 10, wherein the oral administration of the ozonised oil is carried out by the administration of a quantity of ozonised oil from 75 to 1500 mg per day per 70 kg of body weight, preferably from 150 to 1200 mg perday per 70 kg of body weight , more preferably from 200 to 900 mg per day per 70 kg of body weight , most preferably from 450 to 700 mg per day per 70 kg of body weight .12 . Ozonised oil for use according to any one o f claims 3 to 11 , wherein the oral administration of the ozonised oil is carried out for a period of at least one month, preferably from one month to 3 years , more preferably from 2 months to 14 months , most preferably from 5 months to 12 months .13 . Ozonised oil for use according to any one o f claims 1 to 12 , wherein said ozonised oil is administered, preferably orally, in association with at least one conventional therapy for the prevention and / or treatment of AMD .14 . Ozonised oil for use according to claim 13 , wherein said conventional therapy for the prevention and / or treatment of AMD is chosen from anti-VEGF intravitreal inj ections and laser therapy .15 . Ozonised oil for use according to claim 13 or 14 , wherein said ozonised oil is administered before , after, during and / or alternately with said conventional therapy .

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