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  • A61K31/19—Carboxylic acids, e.g. valproic acid
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  • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
• • A—HUMAN NECESSITIES
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  • A61K31/00—Medicinal preparations containing organic active ingredients
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  • A61K31/00—Medicinal preparations containing organic active ingredients
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  • A61K33/00—Medicinal preparations containing inorganic active ingredients
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• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
  • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention relates to the field of treatment of cells of the retinal pigment epithelium (RPE).
• RPE retinal pigment epithelium
• the present invention relates to the use of a composition for the protection of retinal pigment epithelium (RPE) cells, in particular for the treatment of age-related macular degeneration (AMD) or of the disease Stargardt and retinitis pigmentosa in mammals.
• RPE retinal pigment epithelium
• AMD age-related macular degeneration
• Stargardt and retinitis pigmentosa in mammals.
• the object of the invention is to improve the vision of individuals suffering from these diseases or at least to stabilize the course of the disease. State of the art
• AMD Age-related macular degeneration
• Macular function is at the origin of central vision and visual acuity, the high resolution of which is related to its high concentration of cone photoreceptors.
• the early stage of AMD is marked by deposits called Drusen, which affect vision only marginally.
• Subsequent phases include two forms of AMD, geographic atrophy (dry form) or exudative form (wet or neovascular form), the former being much more common than the second.
• the latter stages of both forms lead to the destruction of the macular neurosensory retina, but the course of dry AMD is generally slow, whereas wet AMD can lead to complete blindness within a few weeks.
• Aging is the gradual accumulation over time of changes that are associated with (or responsible for) an increasing susceptibility to the disease.
• a number of degenerative diseases including glaucoma, retinitis pigmentosa, and AMD, may occur as a result of aging.
• Retinitis pigmentosa is a heterogeneous group of genetic retinal degenerations, involving photoreceptors and EPR, and leading to a loss of night vision, then late central vision.
• the specific mechanisms involved in the initiation of different types of diseases related to retinal aging differ, it is believed that the resulting oxidative stress and inflammation are important components that contribute to the pathogenesis.
• EPR cells have several different functions in the eyes: they establish the blood-retinal barrier by their tight junctions, and thus are responsible for the immuno-privileged status of the inner part of the eye bulb; they keep photoreceptors alive by providing nutrients and participating in the visual cycle.
• the current understanding is that a deficiency in the function of EPR cells is at the root of the development of AMD. Aging causes dysfunction of EPR cells and inadequate metabolism, as well as phagocytic activity. Incomplete digestion of the outer segments of the photoreceptors may lead to Drusen formation by reducing diffusion across the Bruch membrane, initially causing deformation of the retina and perceived images.
• Lipofuscins are composed of lipids and proteins, which come from phagolysosomes, lysosomes and photoreceptors. Lipofuscins also contain N-retinyl-N-retinylidene ethanolamine (A2E), which is formed by the condensation of two molecules of retinaldehyde with ethanolamine.
• A2E N-retinyl-N-retinylidene ethanolamine
• Aging is accompanied by increased accumulation of A2E in the retina (Bhosale et al., 2009).
• ⁇ 2 ⁇ generates reactive species that cause damage to proteins, lipids and DNA, and therefore significant oxidative stress in the aging cells of the EPR ( Sparrow & Cai, 2001). These damages disrupt the lysosomal activity of the EPR cells and cause an accumulation of waste, which ends up generating, from place to place, the death of the cells of the EPR which is followed by that of the photoreceptors with which they were associated.
• VEGF Vascular Endothelial Growth Factor
• Dietary supplements have been formulated with generic antioxidant compounds, namely minerals and vitamins with antioxidant properties, for example zinc, vitamins A, C, E, with a real therapeutic effectiveness but limited.
• the AREDS nutraceutical 1 (Age-Related Eye Disease Study, AREDS 2001) is considered the standard of care in the United States for the treatment of dry AMD, reducing the risk of advanced AMD by 25% and the vision loss of 19% over five years.
• Carotenoids molecules exclusively provided by the diet
• lutein, zeaxanthin xanthophylls
• AREDS AREDS formula
• these compounds were tested (alone or in combination) in the AREDS formula, but the results obtained were limited, the supplementation being effective only for a subset of patients deficient in these compounds ( Pinazo-Duran et al., 2014).
• These molecules are effective in vitro for protecting EPR cells (Human D407) against the toxic effects of hydrogen peroxide (Pintea et al., 201 1).
• Japanese patent application JP 2010285364 puts forward a mixture composed of crocetin and another carotenoid that may be a xanthophyll or another diapocarotenoid, ie bixin or norbixin. This mixture, because of its antioxidant properties, is provided for relieving or preventing diseases in which an oxidative phenomenon is involved.
• xanthophylls have also been studied by oral supplementation alone or in combination with lutein and / or zeaxanthin (eg astaxanthin - Parisi et al., 2008).
• Crocins have in vitro photoprotective effect on primary cultures of cattle or primate photoreceptors (Laabich et al., 2006), and crocetin protects neuroganglion cells against oxidative stress (Yamauchi et al., 201 1). Saffran (a crocin / crocetin-rich spice) administered orally has been shown to be active in vivo on the quality of the retina (Maccarone et al., 2008, Falsini et al., 2010, Boisti et al., 2014).
• saffron contains other molecules that may be active on the retina, such as other carotenoids and safranal formed at the same time as crocetin (Verma & Middha 2010, Fernandez-Sanchez et al., 2012). it is difficult to conclude as to the effect of single crocetin.
• Urucum seed extract (Bixaorellana) (Bixilia ® ) showed a photoprotective effect on human skin exposed to UV (FR 2947173, Veillet et al., 2009) and on EPR cells under stress. photooxidant (Fontaine et al., 201 1).
• Bixilia ® extract is a natural extract of Urucum that has been enriched with Bixin.
• Bixilia ® contains other photoprotective phenolic compounds, the presence of which could explain the higher photoprotective activity of the crude extract compared to Bixine alone.
• FR 1 1 54172 (Fontaine et al., 201 1), the protective effect of EPR cells of some of the Bixilia ® extract is analyzed.
• Norbixin in particular its 9'-c / s form, strongly reduces cell death caused by illumination with blue rays of EPR cells pretreated with N-retinyl-N- retinylidene ethanolamine (A2E).
• the present invention provides a composition comprising more than 90% by weight of Norbixin obtained by purification from a seed extract of Bixa orellana, for its use for photoprotection of cells of the retinal pigment epithelium ( EPR) in the mammal.
• EPR retinal pigment epithelium
• seed extract of Bixa orellana an extract prepared from the outer part of the seeds, that is to say the waxy substance covering the seeds of Bixa orellana. This waxy substance is known to be rich in bixin and other minor carotenoids, as well as for its use as a food coloring agent.
• Norbixin bioavailable to mammals after oral administration, is much better absorbed than Bixin and is found in the eye, particularly in the retina.
• the composition comprises more than 90% by weight of Norbixin. In particular embodiments of the invention, the composition comprises more than 95% by weight of Norbixin.
• the composition comprises more than 90% by weight of Norbixin in its 9'-c / ' s form of formula (I):
• the composition comprises at least one element selected from zinc, vitamin C and vitamin E.
• the composition may be used as a dietary supplement or a drug.
• Food supplement means a product containing said composition for the purpose of supplementing the diet by providing nutrients beneficial to health as defined by the European Directive 2002/46 / EC.
• a dietary supplement may be a capsule or tablet to be swallowed or a powder or small ampoule to be mixed with a food and having beneficial effects on EPR cells.
• medicinal product is meant a product containing a precise dose of said compound or said extract according to the definition given by the European Directive 65/65 / EC, namely any substance or composition presented as possessing curative or preventive properties with regard to human or animal diseases .
• the drug containing the compound at therapeutic doses can be administered orally in capsule or tablet form or injected intravitreously or any other route to confer beneficial effects on the retina.
• the composition comprises a carrier acceptable to be ingested, injected into the eye, injected systemically or injected into the blood.
• the composition is administered to the mammal, per day, in an amount of between 0.48 mg / kg of body weight and 48 mg / kg of body weight, preferably of between 0.6 mg / kg of weight. body weight and 20 mg / kg body weight.
• the composition is intended to prevent damage to the retina likely to be caused by exposure to blue radiation.
• blue radiation is meant radiation corresponding to the blue band of the spectrum of visible light, wavelength between 435 nm and 490 nm.
• the composition is for the treatment of age-related macular degeneration (AMD) in the mammal.
• AMD age-related macular degeneration
• the composition is for treating Stargardt's disease and / or retinitis pigmentosa in the mammal.
• Stargardt's disease or Stargardt's syndrome, is a hereditary condition, associating a decrease in bilateral visual acuity with atrophy of the macula, which reproduces, at an early age, the symptoms of the dry form of AMD.
• Figure 1 illustrates the percentage of surviving EPR cells in the presence of N-retinyl-N-retinylidene ethanolamine (A2E) and Bixilia ® or Bixine extract (20 ⁇ ) or Norbixin (20 ⁇ ) after being subject to illumination.
• A2E N-retinyl-N-retinylidene ethanolamine
• Bixilia ® Bixilia ® or Bixine extract (20 ⁇ ) or Norbixin (20 ⁇ ) after being subject to illumination.
• C cyclohexane
• D dichloromethane
• M methanol
• Figure 3a illustrates the plasma concentrations after ingestion of Bixin (left) or Norbixin (right) in C57BI / 6 mice.
• Figure 3b illustrates the pharmacokinetic analysis of Norbixin in C57BI / 6 mice.
• Figure 4 illustrates the HPLC-MS / MS analysis of Norbixin in the eyes of double KO mice (ABCA4 " '' ' , RDH8 " '' ' ) after intraperitoneal injection (10 mg / kg). (3: injected Norbixin, 1 and 2: mono-glucuronides of this compound).
• Figure 5 illustrates the kinetics of ⁇ 2 ⁇ accumulation in the double KO mouse eye (ABCA4 " ' “ , RDH8 “ ' “ ) as a function of age, compared with normal mice.
• Figure 6 illustrates the electroretinograms (left-hand A-wave and right-hand B-wave) of double-knockout KO (ABCA4 " '' ' , RDH8 " '' ' ) mice that received unilateral intravitreal injections of Norbixin (in order to obtain a final concentration in the vitreous 130 ⁇ ), placed for 24 hours in the dark and then exposed to blue light (4000 lux, 1 h). Electroretinograms are performed 7 days after illumination.
• Figure 7 illustrates the number of photoreceptor core layers as a function of distance from the optic nerve in the eyes of treated mice as in Figure 6.
• Figure 8A illustrates the experimental protocol for creating the rat blue light model.
• Figure 8B illustrates the results of the electroretinograms of the rats injected with norbixin (100 mg / kg, 4 injections per rat of a 50 mM solution in NaCl 9% o, 4 rats / series) using the PBN (phenyl-N-tert-butylnitrone, 50 mg / kg, 20 mg / mL solution in 9% NaCl) as a positive control. Electroretinograms are performed 7 days after treatment.
• Figure 9A illustrates the number of photoreceptor core layers as a function of distance from the optic nerve in rat eyes after intraperitoneal injections of alpha-phenyl-N-tert-butylnitrone (PBN) or Norbixin and illumination with a blue light. Histological analyzes are performed 7 days after treatment.
• PBN alpha-phenyl-N-tert-butylnitrone
• Norbixin Norbixin and illumination with a blue light. Histological analyzes are performed 7 days after treatment.
• Figure 9B illustrates the area under each curve of Figure 9A.
• Figure 10 illustrates the amount of A2E accumulated in the double KO mouse eye (ABCA4 " '' ' , RDH8 " ' ' ) having or not ingested food supplemented with norbixin for 3 months.
• Figure 11 shows the electroretinograms of double KO mice (ABCA4 " ' “ , RDH8 “ '' ' ) fed or not fed with food containing 0.3 mg / g pure norbixin for 3 months.
• Figure 12 illustrates the relationship between the amplitude of the electroretinogram (wave A) and the amount of A2E accumulated in the eyes of the double KO mice (ABCA4 " ' “ , RDH8 " ' “ ).
• Figure 13 illustrates the results of reverse phase HPLC analysis of norbixin purified from Bixa orellana extract (isomer identification was performed according to Scotter et al., 1998 and Polar-Cabrera et al. ., 2010).
• the models used in the present invention emphasize the role of N-retinyl-N-retinylidene ethanolamine (A2E) and its phototoxicity. and are, as such, closer to human pathology.
• the tests used in vitro are similar in principle to those used with other natural substances on a human EPR cell line (ARPE-19 cells - Young et al., 2005).
• Bixin 95% by weight pure is prepared from a commercial product (Annatto B) from an organic extraction of Urucum seeds and a Bixin concentration greater than 85% by weight. The purification is carried out by successive recrystallizations.
• Norbixin 95% by weight pure Norbixin is obtained after alkaline hydrolysis of the purified Bixin (5% KOH, 60 ° C., 3 hours). The resulting solution is acidified with concentrated hydrochloric acid and Norbixin is recovered by centrifugation. The pellet is washed twice with water to remove the salts, and the final pellet is freeze-dried.
• This model uses primary cultures of adult pig EPR.
• Cell survival is quantified through a cell viability test.
• the compounds to be tested (in 5 mM solution in DMSO) are added at -48h to obtain final concentrations of 1 to 20 ⁇ ) and then at -19h of ⁇ 2 ⁇ (final concentration 30 ⁇ ) and the cells are irradiated (time Oh). . 24h is measured after the survival of the cells.
• Image acquisition and processing are performed using a fluorescence microscope driven by the Metamorph software and a dedicated quantification program.
• the experiments are carried out on 96 well microplates in quadruplicate and the experiment is reproduced at least four times. The results are expressed as a ratio representing the number of living cells in the wells treated with the test molecules, divided by the number of living cells in the control wells (treated with the dilution medium without A2E).
• FIG. 1 shows that Bixin and Norbixin (20 ⁇ l) effectively protect EPR cells from A2E induced phototoxicity compared to A2E control.
• a crude extract of Urucum seeds diluted to provide 20 ⁇ of bixin has a high photoprotective activity.
• the use of very pure bixin at a concentration of 20 ⁇ made it possible to show that this component actually possessed a significant photoprotective activity (FIG. 1) and that this explained a large part of the activity of the Bixilia extract. ® diluted way to bring the same amount of bixin. Similar activity was also found for Norbixin, which represents the major circulating metabolite of Bixine (Levy et al., 1997). These results are in agreement with the photoprotective activity of these same compounds, previously demonstrated for the photoprotection of human skin (Veillet et al., 2009).
• Bixilia ® contains other photoprotective compounds
• Bixilia ® contains other photoprotective compounds of a phenolic nature, the presence of which could explain the superior activity of the crude extract compared to bixin alone (for the same bixin concentration).
• Sequential extraction of the envelope of the seeds of Urucum was carried out successively with cyclohexane, dichloromethane and methanol (1 L of each / 100 g of seeds). After extraction with cyclohexane, a fraction with a Bixin concentration of 0.65 ⁇ is obtained, after extraction with dichloromethane a fraction is obtained which has a Bixin concentration of 1485 ⁇ l, and after extraction with methanol a fraction which has a Bixin concentration. 45 ⁇ .
• Norbixin in the eyes was investigated in double KO mice (ABCA4 " ' “ , RDH8 “ ' ' ) 3 hours after intraperitoneal injection of Norbixin (10 mg / kg).
• the eyes of 6 animals were dissected and the samples were extracted with acetonitrile, pooled and analyzed by HPLC-MS / MS ( Figure 4), which specifically detected the presence of Norbixin in the EPR. and the retina (Table 2).
• This mouse model two genes involved in the visual pigment cycle (ABCA4 and RDH8) are inactivated, resulting in an early accumulation of A2E in the eyes ( Figure 5).
• This animal model is thus related to human pathology, with, of course, its limits, linked to the differences in the organization of eyes between rodents and primates.
• mice aged 7 weeks were therefore used to perform unilateral intravitreal injections of Norbixin (in order to obtain a final concentration in the vitreous of 130 ⁇ ). After 24 h in the dark, the mice were exposed to blue light (4000 lux, 1 h). The electroretinograms performed 7 days later showed a protective effect of Norbixin, the presence of which allowed to maintain a significant electrical activity as shown in Figure 6.
• the model "rat blue light” consists of subjecting the animals to intense blue light for 6 hours in order to cause ocular damage that is appreciated 7 days later by the realization of electroretinograms then by histological analyzes.
• An antioxidant compound, PBN phenyl-N-tert-butylnitrone
• PBN phenyl-N-tert-butylnitrone
• the compounds whose photoprotective activity is to be determined are injected (intraperitoneally) before and during the illumination phase. This is done with Philips blue neon tubes (4.2 mW / cm 2 ) for 6 hours.
• the experimental protocol is shown in Figure 8A.
• a feed containing 0.3 mg / g of pure Norbixin was prepared and given to double knockout mice (ABCA4 " ' “ , RDH8 " ' ' ) for a period of 3 months.
• the daily dose for significantly slowing retinal degeneration in mice after oral administration is 48 mg / kg body weight. Transposition to humans leads to an active daily dose of 4.8 mg / kg.
• Admissible daily intake or ADI (Adaptive Daily Intake or ADI) of Norbixin is also known to be at most 0.6 mg / kg / day body weight (JECFA / 67 / FC). This value was established on the basis of a no-effect dose or NO (NO) in the rat at 69 mg / kg / day body weight, equivalent to a no-effect daily dose. the man of 11 mg / kg, knowing that no toxicity was observed up to 20 mg / kg / day (Hagiwara et al., 2003).
• the proposed dosage is between 0.48 mg / kg / day and 48 mg / kg / day, ideally between 0.6 mg / kg / day and 20 mg / kg / day.
• Fontaine V, Lafont R, JA Sahel, Veillet S. 201 Use of compounds and composition for the treatment of age-related macular degeneration (AMD).
• Application FR 25506 (filed May 14, 201 1).
• Crocetin prevents retinal degeneration caused by oxidative stress and endoplasmic reticulum stress via inhibition of caspase activity. Mol Cell Pharmacol, 650: 110-119.

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